Derivatives of Ergot-alkaloids: Molecular structure, physical properties, and structure–activity relationships

Journal of Molecular Structure 1024 (2012) 18–31

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Derivatives of Ergot-alkaloids: Molecular structure, physical properties, and structure–activity relationships Bojidarka B. Ivanova ⇑, Michael Spiteller Institut für Umweltforschung, Universität Dortmund, Otto-Hahn-Straße 6, D-44221 Dortmund, Germany

h i g h l i g h t s " Ergot alkaloids. " Structure-properties. " Mass spectrometry. " Quantum chemistry. " Schizophrenia.

a r t i c l e

i n f o

Article history: Received 14 February 2012 Received in revised form 18 April 2012 Accepted 18 April 2012 Available online 18 May 2012 Keywords: Ergot-alkaloids Physical properties Molecular structure Structure–activity relationships

a b s t r a c t A comprehensive screening of fifteen functionalized Ergot-alkaloids, containing bulk aliphatic cyclic substituents at D-ring of the ergoline molecular skeleton was performed, studying their structure-active relationships and model interactions with a2A-adreno-, serotonin (5HT2A) and dopamine D3 (D3A) receptors. The accounted high affinity to the receptors binding loops and unusual bonding situations, joined with the molecular flexibility of the substituents and the presence of proton accepting/donating functional groups in the studied alkaloids, may contribute to further understanding the mechanisms of biological activity in vivo and in predicting their therapeutic potential in central nervous system (CNS), including those related the Schizophrenia. Since the presented correlation between the molecular structure and properties, was based on the comprehensively theoretical computational and experimental physical study on the successfully isolated derivatives, through using routine synthetic pathways in a relatively high yields, marked these derivatives as ‘treasure’ for further experimental and theoretical studied in areas such as: (a) pharmacological and clinical testing; (b) molecular-drugs design of novel psychoactive substances; (c) development of the analytical protocols for determination of Ergot-alkaloids through a functionalization of the ergoline-skeleton, and more. Ó 2012 Elsevier B.V. All rights reserved.

1. Introduction Ergot-alkaloids (ErIAs) was a class of naturally occurred fungalderived indole substances, providing unique opportunity as molecular templates for drugs-design and modelling of semi-synthetic and synthetic derivatives, possessing a pharmacological activity, related the psychoactive function, hallucinogenic effect, treatment the Schizoprenia, and more, affecting the CNS, since these alkaloids have affinity to interact with dopaminergic, noradrenergic, and serotonergic neurons [1,2]. Since one of the model for Schizophrenia, i.e. serotonin model, proposed mutual coherence of the physical illness, cancer and cardiovascular deceases [3], the ⇑ Corresponding author. Tel.: +49 231 755 4089. E-mail addresses: (B.B. Ivanova).

[email protected],

[email protected]

0022-2860/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.molstruc.2012.04.053

Ergot-alkaloids, were no dougth a ‘treasure’ and ‘source’ of novel medications with wide spectrum of biologically active functions. The Ergot-fungus Claviceps purpurea has been found to produce D-lysergic acid (LSD) and ergopeptines which, confer similarity to different neurotransmitters [1], making these natural products (NPs) successful templates for development of protocols for determination, contributing the analytical chemistry in its fundamental and applied aspects as well. So that, from the enormousness interdisciplinary applicability and usefulness the Ergot-alkaloids, in this paper we were focused our efforts in search the novel functionalized derivatives which would be of interest the medicinal chemistry and neuropharmacology. The successfully isolated and elucidated alkaloids (1)–(15) were designed, on the base on a molecular modelling and screening of the structure-activity relationships with 5-HT2A, a1/a2-adreno- and dopamine D1–D3 receptors (Scheme 1). The predicted high receptor affinity, amount

B.B. Ivanova, M. Spiteller / Journal of Molecular Structure 1024 (2012) 18–31

19

Scheme 1. Chemical diagrams and labelling of the studied alkaloids; The theoretical qN(NBO) values, defining the obtained mono-protonated forms of the compounds; The theoretical data of LSD are also shown.

the larger number of designed molecules, using the common concepts and findings of psychoactive biological function and hallucinogenic effect [1,2], the selected groups of chemicals, defined the efforts for searching the optimised biologically oriented synthetic conditions for their successful isolation in a high yields, as well as experimental and theoretical elucidation of their physical properties. Since the natural occurred, synthetic and semi synthetic derivatives were easily convertible to LSD, and so to its diethylamide, we were described the neurotransmitter receptor binding affinity, as an effort to predict the in vivo effects [2], of functionalized amides as potential. The efforts in medicinal chemistry yielded substantial numbers of D3R antagonists, but remarkably only few truly innovative chemicals have been identified [4]. Thus the reported data would be of interest to elucidate the essential features and unusual alkaloid/receptor bonding situations which would improve their inhibitory activity to D3R in particular. Essentially the paper aimed to clarify comprehensively the correlation between the molecular structure and properties of functionalized Ergot-alkaloids as important step for their further application, using the theoretical quantum chemical and experimental physical methods for analysis, so the performed discussion precisely elucidated the observed phenomena, using the advantages of each of the applied approaches.

2. Results and discussion 2.1. Molecular drugs-design, structure–activity relationships and drugs–receptor interactions Since, it was still difficult to design compounds with strongspecific predictable interactions to a given receptor, the major challenge was to clarify some molecular aspects involving common building interactions and untypical binding modes. De facto, the molecular drugs-design and development of receptor-selective

agonists remain largely empirical, somewhat unpredictable and not ready for routine application, nonetheless the powerful computer-aided methods for drug design and quantum chemical approaches. This stage, however was crucial for the biologically oriented synthesis of medications, so that among the major factors considered, those related to the pharmacological activity of a given drug, appeared particularly prominent. Significant role was attributed to molecular conformation, approximations of the drugs-receptor models, but often the obtained results does not corresponded to the global energy minimum, since the higher molecular flexibility allowed the observation of series of closely disposed conformations, both studying the neutral and the protonated forms, often which does not coincided as well. For these reasons amount the successfully applied strategy for drugs-design was the usage of naturally occurred and biologically active substances as templates, providing possibility for functionalization by routine synthetic methods and to involve a specific structural fragments, depending of the molecular conformation of the loops of biologically active macromolecules. Our recent studies in searching of novel potent NPs, using the natural extracts, semisynthetic and synthetic derivatives have been contributed to this statement [5]. The quantum chemical molecular modelling of the drugs-receptor binding provided important information to understand the in vivo processes since allowed a preliminary evaluation of the possibility for atypical specific interactions, physiological conditions, physical properties, and more. In this paper, as common naturally occurred molecular template was used the amide form of ergoline tetracyclic ring skeleton, which as above mentioned were amount most wide distributed forms of these alkaloids in the nature, so that appeared the evolutionary preferred. In terms the medicinal chemistry, when the chemical properties of agonists for a specific receptor were compared with those of the antagonists, the first group of chemicals were relatively small hydrophilic molecules, whereas the antagonists were usually larger and more lipophilic. Thus among the serotonin, and dopamine receptor ago-

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nists, a large distributed functional groups appeared substituted piperidine, piperasine, pyrrolidine, and morpholine, stabilizing as well different protonated forms under physiological conditions [5,6a]. Interestingly, their proton accepting/donating ability depends strongly of the molecular target and the position of small substituents such as ACl, AOH, AOCH3, and/or ANH2 groups [1,2,5], thus contributing additional to the lack of routine prediction of the properties, but providing large perspective for searching and modelling of novel derivatives. In this respect the powerful approaches of the quantum chemistry were also amount the irreplaceable methods for analysis and prediction of molecular properties. It has been discovered in numerous studies, that ErIAs possessed high affinity for a2A-adrenoceptor, dopamine, and nearly all subtypes of serotonin 5-HT receptors. The clinically most effective alkaloids have been found to activate dominantly the 5-HT2A receptors, in some cases may act on 5-HT1B/1D ones and a1/a2-adrenoceptors [2]. So that, herein were consequently described the interactions of these receptors with (1)–(15). Common for (1)–(8) was the obtained p-staking interactions (3.421(0)–3.789(2) Å) of indole fragments (Scheme 1). The potential energy minima were found within 3.4–6.3 kJ/mol. The (1)–(5) were characterised with the conformational minimum of the extended molecular geometry of 5.7– 7.2 kJ/mol. In (6)–(8), (11) and (15), the obtained strong intramolecular hydrogen OH


O bonds (2.456(2)–2.761(7) Å) between amide O-atom and the OH-substituent at R3-position resulted to only one favourable conformer (Scheme 1). The performed NBO analysis, proposed the N5 ((1)–(8)) and N4 (9)–(15) nitrogen from amide fragments as most probable proton accepting centres [6a]. The obtained lowest values of free Gibbs energies (DG) of the protonated forms (( 218.54) ( 255.98) kcal/mol), assumed their preferred stabilization in polar tropic solvents, thus agreed to the experimentally observed easy convertible ability of naturally occurred compounds to simple amides. Theoretical parameters such as rmax, rmin, total solvent accessible surface area of solute, volume of solute cavity, the cavitation, dispersion and repulsion energy as well as total dipole moment of the studied alkaloids were summarised in Table 1. The structure of homology model of the serotonin 5HT2A receptor, based on the b2-adrenergic receptor (Protein Databank (PDB, www.rcsb.org), entry 2RH1 [9], Scheme 2) was used. The optimisation of the intermolecular and receptor interhelical hydrogen bonds were performed, using the alkaloid/receptor molecular complexes [9] (Scheme 2a), where the drugs were localised in an active loop, defined the Phe290.A, Tyr316.A, Phe193.A, Trp286.A, Phe289.A, Ser203.A, and Asp113.A amino acid residues. The molecular conformations in loop were characterised with strong-to-moderate intramolecular hydrogen OH


O bonds (Scheme 2c, 2.675(2)–2.808(2) Å). The ligand-binding sites were sensible towards the molecular skeleton of each of the three sub-types of alkaloids. The (1)–(8) were localised adjacent to Phe290.A and Trp286.A, participating at weak p-interactions (3.488(0)–3.816(2) Å). The dihedral angles, defined by the aromatic planes between the indole fragments in the alkaloids in their ‘close’ conformation and the planes of Phe290.A and Trp286.A residues were 67.8(3)–79.9(4)° and 113.5(8)–88.8(3)°, respectively. Evidence about the stabilized molecular conformation was obtained by the Fs bands (Fig. 1) indicating a weak bathochromic shifting of the emission maxima of about 7-13 nm, in contrast the complete MOs overlapping effect, typical for the classical p-stacking systems and resulting to a shifting of 45 nm. The (9)–(11) occupied similar spaces such those of (1)–(8), overlapping the aromatic regions, and supporting the hypothesis for the main active biological role of the ergoline-residue. The tendency was observed as well for (12)–(15), excluding the COOH-fragment, disposed in an extended manner into the binding pocket (Scheme 2b, Table 3).

The a2-adrenoceptors were involved in many physiological processes through their activation by the neurotransmitters. Among the known subtype-selective agonists and antagonists, as therapeutic mechanism of biological activity related the treatment of hypertension, depression, pain and opioid withdrawal symptoms, their biological role has been associated to a2A-subtype receptor interactions. So that, the alkaloid/receptor interactions were examination using the crystallographic data for rhodopsin ([10a], Protein Databank (PDB, www.rcsb.org), entry 1F88), taking into account the building mode to the second extracellular loops of a2A-adrenoreceptor, contributing to the binding ability the indole alkaloids of type XII [5]. The binding model assumed interactions with Tyr178.A, Tyr268.A, Trp265.A, Phe212.A, Phe261.A and Glu181.A (Scheme 2) [10]. Interestingly, was found that the group of compounds (1)–(8) exhibited dominantly a p-staking effect with Trp265.A(3.677(2)– 3.940(5) Å) with participation of indole fragment at D-ring in the ergoline-residue. In contrast, (12)–(15) were found to build the receptor loop by the moderate (C@O)OH


O(CO)Glu181.A interactions (3.533(2)–3.783(3) Å, Scheme 2c). Similarly to alkaloid/ 5HT2A complexes, the short contacts and non-classical hydrogen bonds were found (Table 3). The development of D3R selective compounds created a formidable challenge for molecular drugs-design the medications with physiochemical properties, since the anti-psychotic drugs were used clinically to treat Schizophrenia, but have been characterised with the multiple side effects that can limit their wide therapeutic application [6]. The known D3R antagonists attenuated drug-seeking behaviours, without associated motor effects, and plausible targets particularly for substance abuse, however, they were characterised with high lipophilic, poor bioavailability and/or predicted toxicity, precluding clinical trials [6]. So that, the reported alkaloids would be of interest as target molecules for development of D3R agonists, due to the presence of polar protic substituents, reducing the lipophilic properties, but keeping the psychoactive residues of the skeleton. Encouraging were the data for (9)–(15), showing atypical receptor building mode, with participation of COOH-group (Scheme 2). The active loop in D3R was defined by helices II, III, V, VI, and VII (Scheme 2), where the molecular interactions were localised within Tyr365.A, Tyr373.A, Trp342.A, His349.A, Phe106.A, Asp110.A, Ile183.A, Ser192.A and Cys114.A (Scheme 2e) residues. Since at physiological pH the monocations showed the favourable amide N4-proton position, the interactions with the receptor were examined comparing the binding modes with the neutral ErIAs [6]. The molecular geometries were weakly affected in (11) and (15), since the intramolecular OH


O hydrogen bonds with R3-OH substituent was observed in the drugs/receptor complexes. The moderate intermolecular (C@O)OH


O(H)Tyr373.A bonds were found (2.876(2)–2.897(9) Å, Scheme 2f). Interestingly, the geometry of the most stable conformer difficult the participation of N+H2 group in interactions with the amino acid residues in the receptor loops. However, an OH


p(Indole) bonds between OH-group in Tyr373.A and aromatic plane of the alkaloids was found. The obtained distances were within the range of 3.577(1)–4.811(6) Å. It is important to note that the studied protonated forms resulted to different binding to the active loop depending of the proton positions, but would described also as hypothetical, since the degradation products were expect under the physiological coordination before the stage of their interactions with the receptors.

3. Physical properties 3.1. Mass spectrometric (MS) data The MS spectra of Ergot-amides have been discussed previously [8], providing several fragmentation schemes and possible

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Table 1 Theoretical rmax, rmin – maxima, respectively, minimal distribution between centre of nuclear charge and isosurface; Stot – total solvent accessible surface area of solute, V – volume of solute cavity; Ecav – cavitation energy, Ed – dispersion energy, Er – repulsion energy, DGsolv – Gibbs free energy, and ltot – total dipole moment of the studied ErIAs.

rmax, Å rmin, Å Stot, Å2 V, Å3 Ecav., kcal/mol Ed, kcal/mol Er, kcal/mol DGsolv., kcal/mol ltot, D

DGsolv : a, kcal/mol

rmax, Å rmin, Å Stot, Å2 V, Å3 Ecav., kcal/mol Ed, kcal/mol Er, kcal/mol DGsolv., kcal/mol ltot, D

DGsolv : a, kcal/mol

rmax, Å rmin, Å Stot, Å2 V, Å3 Ecav., kcal/mol Ed, kcal/mol Er, kcal/mol DGsolv., kcal/mol ltot, D

DGsolv : a, kcal/mol

(1)

(2)

(3)

(4)

(5)

11.23 3.07 1324.17 1965.13 39.66 44.15 50.50 132.15 17.0411 5HT2A-(1) 351.9 a2-(1) 466.8 D3-(1) 881.1

13.76 3.00 1235.52 1992.44 37.12 48.13 50.11 132.16 18.0289 5HT2A-(2) 488.61 a2-(2) 577.9 D3-(2) 901.2

14.13 4.09 1178.24 2001.13 40.40 39.00 34.10 117.18 17.2231 5HT2A-(3) 123.01 a2-(3) 321.7 D3-(3) 905.2

15.66 4.01 992.95 1997.87 38.21 39.98 39.09 122.01 10.0251 5HT2A-(4) 200.75 a2-(4) 890.6 D3-(4) 870.5

14.59 5.01 1055.14 1675.13 37.20 45.60 40.12 156.12 17.0099 5HT2A-(5) 300.61 a2-(5) 552.1 D3-(5) 908.2

(6) 11.23 3.97 1267.17 1819.12 40.15 55.23 66.01 200.13 14.0005 5HT2A-(6) 367.5 a2-(6) 335.4 D3-(6) 300.1

(7) 13.01 4.03 1304.42 1833.27 37.13 57.10 62.11 177.13 12.0253 5HT2A-(7) 400.8 a2-(7) 1190.3 D3-(7) 879.2

(8) 12.06 5.02 1321.27 1865.19 35.15 36.01 67.13 108.09 11.0033 5HT2A-(8) 561.2 a2-(8) 809.4 D3-(8) 700.1

(9) 16.21 6.31 1090.16 1885.25 35.20 35.11 70.22 122.55 7.0255 5HT2A-(9) 155.2 a2-(9) 801.2 D3-(9) 338.7

(10) 13.21 4.11 1100.91 1807.24 37.03 45.13 44.17 148.11 7.0116 5HT2A-(10) 322.1 a2-(10) 110.7 D3-(10) 144.8

(11) 15.25 3.37 809.12 1101.25 67.10 42.12 50.09 341.12 7.5561 5HT2A-(11) 988.2 a2-(11) 1000.9 D3-(11)

(12) 16.17 3.08 892.31 1100.72 90.22 97.23 59.11 180.05 4.5673 5HT2A-(12) 488.61 a2-(12) 907.8 D3-(12) 987.3

(13) 18.13 3.52 1090.16 1076.51 90.78 40.10 11.10 19.18 4.2211 5HT2A-(13) 123.01 a2-(13) 778.3 D3-(13) 900.8

(14) 19.22 3.39 1000.10 1231.17 54.10 56.10 60.40 40.06 5.7789 5HT2A-(14) 200.75 a2-(14) 445.7 D3-(14) 600.8

(15) 18.24 4.75 1009.15 1017.15 60.11 60.12 90.06 49.10 5.0028 5HT2A-(15) 300.61 a2-(15) 328.9 D3-(15) 782.1

a The comparison of the DG energy of the isolated ErIAs and the receptor-ErAIs complexes should performed as tendency for change of the values, not as absolute values, according the errors of the DFT IPCM (resp. PCM) and MD methods.

mechanisms depending of the type of amide fragments. The advantages of the applied HPLC-ESI-MS both in single and tandem mode as well as the MALDI-MS methods have a broad definition and were irreplaceable both for structural analysis of the isolated products, corresponding intermediates and degradation products at the different synthetic pathways. The observed peaks at m/z 268 [C16H18N3O]+ and 70 [C4H8N]+ were presented in the spectra of the isolated alkaloids and were associated the ergoline skeleton [8]. The data confirmed the obtained theoretically qN(NBO) values (Scheme 1), proposing as most preferred proton accepting position the amine N5-nitrogen, which resulted to an easy molecular fragmentation and stabilization of the shown in Fig. 3 cations. The DG within ( 65.7) ( 73.8) kcal/mol were found and explained the relatively low-intensive peaks [8] in the experimental mass spectra of this class of alkaloids, in a similar way as those obtained for alkaloids of type XII [5]. It is important to discuss that the presented theoretical data were assigned to the ionic species observed experimentally in our derivatives (Fig. 3) comparing to other

possible ones already reported for Ergot-alkaloids [8]. Nevertheless that for some classes of naturally occurred and semi-synthetic analogous such as indole alkaloids of type I, III, and VI the theoretical data for DG, using the same mixed-solvation approach, were showed tendency that the entropy factor appeared as dominant [5]. The origin of the obtained difference need further systematic study, also object of discussion currently, and would be essentially in the fact that the experimental data were occurred under high vacuum conditions, where the isolated ions were not in thermal equilibrium, in contrast to the reported theoretical data about the ionic species defining the tabulated quantities at the global minimum of the energy in equilibrium. Nonetheless, the wellestablished quantum chemical theory supported sufficiently the experimental data about the protonation processes and fragmentation behaviour of the studied systems, since our efforts were localised into assignment of the observed peaks of molecular ions to possible most stable in gas-phase charged species at given elemental composition. Nevertheless, that (1)–(15) were prepared by the

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Scheme 2. Interhelical hydrogen bonds formed spontaneously during simulations are given as blue lines in the structure of the homology model of the serotonin 5HT2A receptor (a), based on the b2-adrenergic receptor (Protein Databank (PDB, www.rcsb.org), entry 2RH1 [9], as well as ErIAs-protein interactions in receptor’s loop; Hydrophilic solvent accessible surfaces in the protein-alkaloid molecular complexes are shown in the molecular complexes with the alkaloid (1)/5HT2A (b), respectively; The structure of the a2A-receptor, using the crystal structure of rhodopsin ([10a], Protein Databank (PDB, www.rcsb.org), entry 1F88) (c), as well as ErIAs-protein interactions in a2A-receptor in the loop of (12); Hydrophilic solvent accessible surfaces in the protein-alkaloid molecular complexes are shown in the molecular complexes with the alkaloid (12)/a2Areceptor (d); Hydrophilic solvent accessible surfaces in the protein-alkaloid molecular complexes are shown in the molecular complexes with the neutral form (e) and protonated one (f) of alkaloid (12)/D3; The hydrogen bonding scheme in the alkaloid/D3 molecular complexes are shown with blue lines. The molecular structure of the D3 was obtained from the Protein Databank (PDB, www.rcsb.org), entry 3PDL [6a]).

successive from 4,6-dihydro-indolo[4,3f-g]quinoline-9-carboxylic acid methyl ester (I) (Scheme 2), using the modified synthetic scheme [7a–7k], through the formation of azides in acidic medium and further condensation of the bases [7l], the synthetic step of the isolation of intermediate as bases for formation the final products was appeared successful only in (9)–(15). The reported shorted synthetic partway to obtaining of ethyl ester, through the 6-hydroxyl-4,6-dihydro-indolo[4,3f-g]quinoline-9-carboxylic acid methyl ester, achieved as intermediate from 6-formyl-5-(4-indolyl)-nicotinic acid ethyl ester [7m,7q], resulted to yield of R1-substituted alkaloids within 5–8% accompanied with parallel formation of unwanted cyclic adducts explained as result of the base reaction medium [7m,7q]. The molecular structure of these products were elucidated also both quantum chemically as well as mass spectrometrically (Fig. 3b), but the obtained model interactions with the studied receptors indicated that these compounds were not geometrically suitable to the active loops. It is important to discuss further this stage of the synthetic scheme since under the modified experimental conditions in the presence of the k CH3COOH and ZnCl2, still the isolation of Id, obtained from Ic was accompanied with the formation of adduct labelled as Id-a (Scheme 2), which would explain the obtained low yields of the intermediate. Thus as shown in Fig. 3 the mass chromatogram of Ic, revealed three peaks at the RT of 7.15, 7.50 and 8.05 min, corresponding to the intermediate Ic and the non-reacted starting chlorinated reagents Ia and Ib according the described procedure, which were defined unambiguously by the isotope ratios of the peaks at the m/z 268 [C13H15O3NCl]+ and 199 [C9H7O3Cl]+ respectively. The further treatment the Ic under the shown conditions resulted to observation of the mass chromatogram with peaks at the RT at 8.75/8.88 and 9.73 min, with ESI spectra (Fig. 3c), characterising with the peaks at the m/z 395.17 of the Id and 407.24 compound Id-a with elemental composition [C22H20O6N2]+, which would assigned to

the shown structure. The observed double peak at 8.75/8.88 min was characterised with the electronic spectra shown in same figure, correlating to the obtained theoretical values of 444.96 (f = 0.2677), 362.31 (f = 0.0153) and 338.37 nm (f = 0.0095), and assumed to two conformations of the Id-a. In contrast the synthesis of R1-substituted ergoline-fragment from the 3-(1-benzoyl6-hydroxy-2,3-dihydro-1H-indol-2-yl)-propionic acid, through the 4-acetyl-7-methyl-4,5,5a,6,6a,7,8,9-octahydro-indolo[4,3fg]quinoline-9-carbonitrile, followed the formation of 9-COH, which using the Mannich reaction was transform to 9-COCH3 derivatives [7n] yielded the 23–26% of the intermediates. Nevertheless that the yields of formation of (1)–(15) were within 15– 44%, preventing their potential serious manufacturing, like other synthetic Ergot-alkaloids, of crucial importance at this stage of the understanding the mechanism of their interactions with different receptors, aiming in vitro and in vivo studies of obtained representative most effective analogous, allowing further optimisation the synthetic pathways according the needs the pharmaceutical manufacturing. 3.2. Electronic absorption and fluorescence spectra Typical for the indole alkaloids [6] were the electronic transitions and related optical phenomena, localised within the frame of the conjugated indole system. The absorption bands were identified within the spectroscopic region of 200–330 nm, and the theoretically obtained values agree reasonably well with the experimental data of the diluted solutions (Fig. 1, Table 2). With increasing of the concentration, the indole p-staking effects resulted to a bathochromic shifting of the highest wavelength maximum within 7-25 nm, depending of the substituents [5] as shown in (1)–(8), (11) and (15), where bands within 225–230 (molar extinction coefficient (em) 25,800 L mol 1 cm 1), 245–250

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HO OH

O

NH O

HO

OH

O

O

NH O

O

NH O

NH O OH

N H

N H

CH3

N

HO

CH3

N

N H

HO

NH

HO

NH

NH

N H

HO N H

N H

(2)

N H

(3)

(4)

HO O

HO OH

O

NH O

OH

O

NH O

O

NH O

N H

CH3

N

N H

H3CO

H3CO N H

N H

(6)

N H

(7)

O

OH

(8)

O

OH

OH

OH

O

O

CH3

N

NH H3CO

N H

(5)

N H

CH3

N

NH

HO

O

OH

N H

CH3

N

NH

NH

NH O

OH

OH H3CO

CH3

N

NH HO

HO

(1)

N H

CH3

N

O

O

OH N H

CH3

N

N H

HO

N H

CH3

N

HO

N H

NH

NH

HO N H

N H

N H

(10)

OH

(11)

O

O O

O

O

OH

OH N H

CH3

N

N H

CH3

N

HO

N H

CH3

N

HO N H

(13)

N H

(12)

OH

OH

O

CH3

N

NH HO

(9)

O

CH3

N

N H

N H

(14)

(15)

Fig. 1. The solvent accessible surfaces and most stable conformers of the isolated alkaloids (1)–(15); Chemical diagrams of the studied alkaloids.

(em, 25,000 L mol 1 cm 1) and 330-348 nm (em, 5300 L mol 1 cm 1) were observed and assigned to the stabilized ‘close’ form of the

alkaloids. The observed electronic absorptions (EAs) maxima, remaining practically constant within the studied concentration

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Table 2 Theoretical and experimental electronic absorption, CD and fluorescence spectra in acetonitrile; kmax (nm), em (L mol 1 cm 1); f and r-oscillatory and rotatory strength; kex = 365 nm; [aD] (T = 24.02–24.11 °C); The fluorescence spectra of isolated molecules and molecular complexes with serotonin receptor; r-values, obtained by the non-linear mathematical approach. Electronic absorption data kmax

em

kmax

f

CD-spectra

Fluorescence

kmax (r)

[aD] Experimental

Experimental

Theoretical

Experimental

225 238 246 284 293

10 345 9 879 7342 7000 4861

225

0.8921

215 (+2.7)

233 (+4.5)

282 296

0.7811 0.0771

227

9875

221

0.6592

220 (+2.0)

244 280 301

9800 7421 4002

283 304

0.5554 0.0421

(3)

211 231 250 297

6832 7223 5557 2100

225 247

0.4219 0.0.671

301

0.0032

(4)

223 234 262 299

10,065 9822 7940 1097

224 246

0.7651 0.1056

301

0.0784

(5)

221 239 258 289 300

10,103 10,156 9541 9001 805

224 251 290

(6)

222 256 270 296 304

9087 9005 7321 7000 2314

(7)

209 236 248 298 301

(8)

(1)

Molecule

Drug/receptor complex

282 (+23.7)

292 (+28.4)

147.5°

21°

399

402/411

247 ( 11.3)

285 (+12.46)

300 (+1.0)

100.4°

55. 2°

393

398/407

220 (+4.2)

240 ( 8.9)

289 (+2.2)

310 (+33.6)

122.2°

100. 7°

394

396

223 (+32.2)

246 ( 25.1)

255 ( 1.8)

292 (+15.7)

307 (+33.7)

78.8°

97. 3°

386

398/406

0.8853 0.2451 0.0561

222 ( 9.8)

238 ( 12.7)

266 (+23.3)

293 ( 1.0)

300 (+6.2)

84.6°

56. 9°

399

407/413

227 267 289

0.4521 0.5689 0.0043

221 ( 11.9)

234 ( 17.6)

248 (+1.2)

288 ( 0.6)

311 (+1.9)

28°

20°

400

403

10,801 8754 4581 1671 1093

224 266 300

0.5421 0.4430 0.0071

-

-

256 (+27.8)

290 ( 34.1)

320 (+0.9)

33°

18°

396

390/408

210 227 248 296

11,876 9072 9002 1231

224 247

0.8971 0.7782

220 ( 16.8)

-

237 (+19.7)

292 ( 46.1)

307 (+0.2)

16°

42°

397

406,413

305

0.0015

(9)

223 252 289

21 256 5598 1081

221 244 300

0.8752 0.7712 0.0045

220 ( 21.4)

231 ( 15.3)

255 (+11.7)

292 ( 4.7)

340 (+0.9)

45.6°

17.8°

394

397/402

(10)

224 258 304

17,652 8931 2236

227 248 295

0.5331 0.5543 0.0018

226 ( 1.3)

249 ( 10.3)

-

297 ( 16.3)

313 (+7.2)

11.2°

12.8°

399

392

(11)

227 243 307 311

18,551 4421 2873 1075

224 250 304

0.6622 0.5552 0.0105

225 ( 18.5)

237 ( 17.5)

288 (+18.1)

-

300 (+0.1)

32.6°

30.1°

395

390

(12)

222 277 290

17,304 15,662 4305

228 255 297

0.5213 0.4412 0.0011

224 ( 0.2)

248 ( 28.9)

-

298 ( 13.3)

309 (+4.5)

90.8°

33.1°

397

400/407

(13)

225 246 293

17,541 8890 9021

227 249 304

0.8890 0.6609 0.0013

224 ( 10.6)

246 ( 5.1)

-

304 ( 11.3)

-

13.1°

0.6°

399

391/417

(14)

222 259 277

17,090 15,661 6668

227 249 283

0.0672 0.0513 0.0010

-

237 ( 29.2)

270 (+60.3)

299 ( 11.5)

321 (+0.3)

18.1°

10.3°

391

399

(15)

223 244 280 294

18,902 17,002 5690 4421

224 247 288 296

0.0892 0.0932 0.0010 0.0007

215 ( 9.1)

230 ( 13.1)

-

300 ( 14.2)

315 (+0.3)

141.7°

60.2°

389

395/417

(2)

270 ( 5.24)

kem Theoretical

region (Fig. 1), were characterised with the pairs of bands at about 220 (em, 25,100 L mol 1 cm 1), 240 (em, 19,600 L mol 1 cm 1) and

310 nm (em, 7500 L mol 1 cm 1) as well as the Fs bands within the range of 395–415 nm. These data assumed an existing of the

25

B.B. Ivanova, M. Spiteller / Journal of Molecular Structure 1024 (2012) 18–31

Table 3 Theoretical interhelical bonds (including classical hydrogen bonds as well as short contacts) in MM/MD simulations as well as ErIAs-receptor interactions; Bond lengths are given in Å; The corresponding distances are shown between the heavy atoms. ErIAs/5HT2A (1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)

(11)

(12)

(13)

(14)

(15)

Phe290.A(p-stacking) Trp286.A(p-stacking)

3.813 3.422

3.244 -

3.303 3.611

3.559 3.446

3.223 3.365

3.077 3.222

– 3.713

3.455 3.871

2.979 –

2.897 –

3.200 3.401

3.369 3.209

3.553 3.009

3.222 3.602

– 2.902

Trp265.A(p-stacking) (C@O)OH


O(CO)Glu181.A

ErIAs/a2A 3.677 3.711 – –

3.892 –

3.940 –

3.702 –

3.700 –

3.834 –

3.906 –

– –

– –

– –

– 3.533

– 3.783

– 3.755

– 3.667

(C@O)OH


O(H)Tyr373.A OH


p (Indole) Tyr373.A

ErIAs/D3 2.876 2.882 – –

2.898 –

2.895 3.577

2.890 –

2.885 3.918

2.871 4.812

2.877 3.700

– –

– –

2.875 3.985

– –

2.904 –

– 3.890

– 3.580

different molecular conformations in solution defined from the flexibility of the molecular chains. Same optical phenomena were found in the EAs in solution (Table 2). The functionalization of the alkaloids by the conjugated p-systems appeared also an important point for the optical phenomena of these alkaloids, since the interaction between agonists and active receptors sites were characterized mainly via hydrophobic p–p stacking effects [2] and effected batochromically both the EAs and Fs bands.

3.3. Circular dichroic (CD) spectra CD spectroscopy was used to analyze the isolated Ergot-alkaloids by correlating the stereochemistry of these compounds with the sign of certain CD Cotton effects (CEs) (Table 2, Fig. 2). The interaction of the electric transition moments of the indole chromophores lead to CD bands which can be directly related to molecular configuration and conformation. Similar the chiral chromatography and mass spectrometry the CD spectroscopy was applied both for the study of the isolated compounds as well as at the different stages of the synthetic pathways. The bisignate curve at about 228 nm and 240 nm in the CD spectra arises from exciton coupling of the conjugated with the double bond indole transitions and the sign of the couplet was directly related to the molecular configuration. The studied set of compounds allowed analysis of other non-coupled CD bands. Additional theoretical CD spectra have shown the utility of CD for obtaining conformational information. A more accurate evaluation of the intensity of the bisignate CD profile arising from exciton coupling between the indole ring and the conjugated double bond as well as effecting of the presence of second indole substituent in the compounds (1)– (11) was gained by curve-fitting the CD contributions due to the inherent chirality. The p-staking effect yielded the difference CD spectra more typical for the concentrated solutions of the indole containing systems and CD spectra of NPs in solid-state [5]. In general, the subtracted CDs curves with bands at 225 and 240 nm were more symmetric than the original experimental curves, which would explain with the applied Gauss-function (Fig. 2). Since the CD contains other CEs in addition to the bisignate curve, it is apparent that either the new environment in which the indole chromophores were placed lead to new non-coupled CEs, or that other weaker coupling of indole transitions was occurring (Fig. 2). In addition to the exciton couplet, two CEs were presented at about 255–270 and 300-320 nm, respectively. The CEs at the first group was derived from the indole, transition 1La as shown from the calculated electronic transitions within the frame of the indole chromophore in the Cs-symmetry. The second band region would assigned to the overlapped 1La and 1Lb as well as only 1Lb transitions, perturbed batochromically in the cases of the intramolecularly configurationally ‘‘closed’’ p-staked alkaloids (1)–(11). Last CEs were found as relatively weak, especially above 300 nm

(De = (+0.3) (+4.5°)). Nevertheless that in the cases of (1), (3) and (4) the De values within (+28.4) (+33.7o) were found. Comparison of the varying CEs observed in the experimental and theoretical CD spectra led to no clear cut correlation influencing this band, appeared sensitive of the environmental effects. The discussed results clearly showed that the interpretation the molecular configuration in terms the experimental CD spectroscopic patterns would be also source of the errors both in terms the sign of the Cotton effects as well at the CD band positions, especially for the effects in the cases of the strongly overlapped patterns where by conventional techniques was difficult to define the precise spectroscopic quantities as shown band at 223 nm in Fig. 2. So that, the obtained differences between the theoretical and experimental [a]D values should interpreted also in terms the sources of errors from the assignment of the experimental patterns, including the errors of the chemometric approaches, due to the broad and overlapped characters of the bands in the CD spectra. Nevertheless that comprehensively were discussed mainly the sources of the errors of the theoretical methods [11s,11t,11u,11v], the studied alkaloids provided also the theoretical and experimental evidences about the high accurate prediction of the electronic transitions by the shown theoretical approaches, due to the obtained differences of kmax of 1 nm for some of studied molecules, but the CD spectroscopic data at the same theoretical levels would resulted to significant differences, even using chemometric approaches at level of confidence r2 > 99%. It is important to mention that the non-linear approaches were further tested by the comparative first and second derivative analysis as a classical (Fig. 2) approaches for determination the bands positions. For the complex spectroscopic patterns the obtained differences within the 1–4 nm between the chemometric approaches at the level of confidence of r2 > 99% were within the frame of the errors the applied theoretical methods, meaning that for the assignment of the CD spectroscopic complex patterns it is difficult to define unambiguously the origin of the obtained differences between the theoretical and experimental data, even in the cases when a modelling of the polar environment by the PCM and/or mixed theoretical models. Since these aspects of the discussed results were crucial for the development of the analytical protocols for accurate and precise qualitative and quantitative determination, taking part of the validation procedures, of these and other classes of naturally occurred, semi-synthetic and synthetic products, they were/are presented for each of applied analytical methods in resent studies in the field [5e–5h,12f].

4. Experimental 4.1. Synthesis The derivatives (1)–(15) were obtained using the condensation of the indole substituted 4,6-dihydro-indolo[4,3f-g]quinoline-9-car-

26

B.B. Ivanova, M. Spiteller / Journal of Molecular Structure 1024 (2012) 18–31

40

12 10

20

8 6

CD [mpeg]

CD [mpeg]

0 -20 -40

(12) (1b) (1) (3) (4)

-60

4 2 0 -2 -4 -6

-80 200

300

200

400

300

400

λ [nm]

λ [nm]

(a)

(b) 40

40 20 0

0 2

χ /DoF = 2.12962

-20

2

CD [mpeg]

CD [mpeg]

20

-20 -40 -60

r = 0.99356

2

χ /DoF = 1.67209

-80 -40

2

r = 0.99069

-100 -120

-60 200

250

300

350

400

450

λ [nm]

(c)

200

300

400

λ [nm]

(d)

Fig. 2. Experimental CD spectra in solvent mixture methanol:n-propanol = 4:1 (a); The curve (1a) was obtained by adding to the solution of (1) the 2M HCOOH at the molar ratio alkaloid : acid 1:10; Mathematically procedures CD spectra; The first (black solid-dots line) and second derivative (blue solid-dots line) CD curve of the (1); The experimental reference pattern was given with the red solid line (b); The non-linear curve fitted CD spectrum of (3) after the application of the multi-point baseline correction method (c) and without the preliminary baseline correction (d); The regression coefficients were shown. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

boxylic acid methyl ester (I), appropriate 3-chloroacetylated cyclohexyl (indole) derivatives (0.176–0.200 mL), and K2CO3 (147.1 mg) in DMF (2 mL). The obtained mixtures were stirred and microwave irradiated under the following conditions: 10 min at 200 W. In addition the reaction mixture was heated continuously at the 100 °C for 2  12 h, than was quenched with NaHCO3 saturated aqueous solution (10 mL) and extracted with ethyl acetate (3  10 mL). The organic phases were dried over dry Na2SO4. After removal of the solvent under reduced pressure, the residue was crystallized from ethanol [7]. The (I) was obtained by pathway, depicted in Scheme 2. The Ib was obtained when to a solution of pyridine-2,5-dicarboxylic acid dimethyl ester (5.90 g) in 100 ml methanol was added Cu(NO3)2 (14.0 g) in a 200 ml round bottom flask equipped with a reflux condenser and a stirring bar for 2 h. The violet precipitation was observed after 20 min and lasted throughout the course of the reaction. The reaction was cooled to room temperature and the reaction mixture was reduced to 1/3 of its original volume. The precipitate was collected by filtration and washed with cold methanol. To a solution/s of EtMgBr (10 ml in ether) was added a solution Ia (3.00 g) in ether (anhydrous, 20 ml). The resulting two-phase system was stand for 15 min under stirring whereupon ZnCl2 (15 ml in ether). The two-phase system/s were stand for 30 min when Ib (3.2 g) in anhydrous ether (10 ml) was added rapidly under vigorous

stirring. The reaction mixture/s were stand for 2 h whereupon NH4Cl was added. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic layers were washed with NaHCO3 followed by brine (25 mL), and dried over Na2SO4. Removal of the solvent in vacuum afforded a yellow powder of Ic. The If was obtained by I using the procedure in [7o], while the removing the Boc-protection of the N-indole functional fragment was obtained according the [7p]. The compounds (1)–(8) in the strong acidic medium polar protic solvents were unstable and resulted to the isolation of proposed cyclic products which were analysed with the CD spectroscopy and mass spectrometry (Fig. 2, compounds (1b), derivative the (1)). The mechanism of the proposed cyclisation under discussion. Moreover the process was associated with the chiral transformation (Fig. 2a). 7-Methyl-4,6,6a,7,8,9-hexahydro-indolo[4,3f–g]quinoline-9-carboxylic acid [1-(2-hydroxy1-methyl-ethylcarbamoyl)-2-(1H-indol-3-yl)-ethyl]-amide (1): 1 H-NMR (600 MHz, CD3CN), d, [ppm]; J, [Hz]: 2.56 (t, 3H, CH3), 2.78–2.92 (m, 4H), 3.12 (m, 1H), 4.02 (s, 3H); 4.95 (s, 2H), 4.70– 5.20 (m, 5H), 6.90 (d, 1H, J = 8.0), 7.56 (t, 1H, J = 7.9), 7.72 (s, 1H), 7.77 (d, 1H, J = 8.0), 8.05 (s, 1H), 7.76, 8.10, 8.12 (s, 3H), 9.44 (d, 1H, J = 1.6), 9.40 (d, 1H, J = 1.6); 13C-NMR (125 MHz, CD3CN): d, 33.6, 35.5, 36.0, 38.1, 51.5, 55.1, 57.7, 59.3, 61.3, 62.7, 62.3, 63.4, 105.2, 111.0, 120.5, 121.3, 123.5, 124.0, 127.2, 129.0, 136.1, 140.3, 146.0,

B.B. Ivanova, M. Spiteller / Journal of Molecular Structure 1024 (2012) 18–31

27

Fig. 3. Electronic transitions of (12) in acetonitrile: methanol = 1:1 with the recalculated pH region for the studied solvent mixture equivalent the 5.7–9.3 and the mass chromatogram (a); ESI-MS/MS spectrum of (12) (b); chemical diagram and fragmentation scheme; The protonated forms of the ionic fragments are obtained according the shown qN(NBO) values of the corresponding neutral species; The potential energies (E) are given in [a.u.] an corresponded to the charged moieties calculated using the mixed solvation approach (a); Mass chromatograms and ESI-MS spectra of Ic (b) and Id (c), respectively.

147.0, 150.5, 164.2, 183.1, 182.9; Yield, 15.5%; MS: 512.782 ([M + H]+); Found, C, 70.22; H, 6.42; Calcd. [C30H33N5O3]+, C, 70.43; H, 6.50; 1-Hydroxy-7-methyl-4,6,6a,7,8,9-hexahydro-indolo[4,3f– g]quinoline-9-carboxylic acid [2-(5-hydroxy-1H-indol-3-yl)-1-(2hydroxy-1-methyl-ethylcarbamoyl)-ethyl]-amide (2): 1H-NMR, d, J: 2.57 (t, 3H, CH3), 2.78–2.90 (m, 4H), 3.22 (m, 1H), 4.05 (s, 3H); 4.96 (s, 2H), 4.70–5.20 (m, 4H), 6.90 (d, 1H, J = 8.0), 7.57 (t, 1H, J = 8.0), 7.75 (s, 1H), 7.76 (d, 1H, J = 8.1), 8.07 (s, 1H), 7.77, 8.09, 8.10 (s, 3H), 9.45 (d, 1H, J = 1.5), 9.41 (d, 1H, J = 1.6), 10.3, 10.6 (s, 2H); 13C-NMR, d, 33.4, 35.1, 36.0, 38.0, 51.3, 55.0, 57.5, 59.2, 61.3, 62.9, 67.5, 68.1, 104.8, 110.6, 119.6, 120.2, 125.2, 125.4, 126.9, 129.2, 136.0, 141.5, 146.2, 148.2, 150.5, 165.1, 183.0, 183.8; Yield, 18.2%; MS: 544.109 ([M + H]+); Found, C, 66.23; H, 6.10; Calcd. [C30H33N5O5]+, C, 66.28; H, 6.12; 1-Hydroxy-7-methyl-4,6,6a,7,8,9hexahydro-indolo[4,3f–g]quinoline-9-carboxylic acid [2-(5-hydroxy-1H-indol-3-yl)-1-(1-hydroxy-propylcarbamoyl)-ethyl]-amide (3): 1H-NMR, d, J: 2.21 (m, 3H, CH3), 2.67–2.92 (m, 4H), 3.20 (m, 1H), 4.09 (s, 3H); 4.95 (s, 2H), 4.72–5.25 (m, 4H), 6.92 (d, 1H, J = 8.0), 7.55 (t, 1H, J = 8.1), 7.76 (s, 1H), 7.77 (d, 1H, J = 8.0), 8.06 (s, 1H), 7.75, 8.10, 8.11 (s, 3H), 9.47 (d, 1H, J = 1.4), 9.40 (d, 1H, J = 1.5), 10.2, 10.7 (s, 2H); 13 C-NMR, d, 33.3, 35.6, 36.3, 38.2, 51.6, 55.2, 57.8, 59.1, 61.5, 63.0, 67.6, 68.0, 105.9, 111.5, 120.7, 120.0, 125.1, 126.5, 127.8, 130.3, 136.3, 143.3, 147.1, 149.0, 151.6, 166.0, 184.8, 184.7; Yield, 13.7%; MS: 545.008 ([M + H]+); Found, C, 66.10; H, 5.98; Calcd. [C30H33N5O5]+, C, 66.28; H, 6.12; 1,9-Dihydroxy-7-methyl-

4,6,6a,7,8,9-hexahydro-indolo[4,3f–g]quinoline-9-carboxylic acid [2-(5-hydroxy-1H-indol-3-yl)-1-(1-hydroxy-propylcarbamoyl)ethyl]-amide (4): 1H-NMR, d, J: 2.21 (m, 3H, CH3), 2.67–2.92 (m, 4H), 3.20 (m, 1H), 4.09 (s, 3H); 4.95 (s, 2H), 4.70–5.26 (m, 3H), 6.98 (d, 1H, J = 8.1), 7.59 (t, 1H, J = 8.0), 7.75 (s, 1H), 7.78 (d, 1H, J = 8.0), 8.05 (s, 1H), 7.77, 8.11, 8.13 (s, 3H), 9.44 (d, 1H, J = 1.5), 9.45 (d, 1H, J = 1.6), 10.5, 10.8 (s, 2H); 13C-NMR, d, 33.0, 35.8, 36.5, 38.9, 51.5, 55.6, 57.9, 59.4, 63.2, 63.9, 67.9, 68.3, 106.7, 112.1, 121.5, 121.3, 126.8, 126.9, 128.2, 131.5, 137.9, 144.3, 148.2, 149.0, 150.5, 172.2, 185.4, 185.2; Yield, 14.8%; MS: 559.783 ([M + H]+); Found, C, 64.27; H, 5.91; Calcd. [C30H33N5O6]+, C, 64.39; H, 5.94; 7-Methyl4,6,6a,7,8,9-hexahydro-indolo[4,3f–g]quinoline-9-carboxylic acid [1-(1-hydroxy-propylcarbamoyl)-2-(5-methoxy-1H-indol-3-yl)ethyl]-amide (5): 1H-NMR, d, J: 2.20 (m, 3H, CH3), 2.67–2.61 (m, 4H), 3.23 (m, 1H), 3.56 (s, 2H, OCH3), 4.11 (s, 3H); 4.97 (s, 2H), 4.72–5.30 (m, 3H), 7.00 (d, 1H, J = 8.0), 7.63 (t, 1H, J = 8.1), 7.76 (s, 1H), 7.77 (d, 1H, J = 8.2), 8.07 (s, 1H), 7.79, 8.10, 8.15 (s, 3H), 9.48 (d, 1H, J = 1.7), 9.49 (d, 1H, J = 1.5); 13C-NMR, d, 33.0, 35.4, 35.7, 38.3, 44.6, 51.0, 55.6, 57.9, 59.4, 63.2, 63.9, 64.2, 66.6, 106.5, 112.0, 121.1, 122.7, 126.1, 127.3, 128.9, 130.2, 139.1, 144.2, 145.1, 147.9, 151.3, 170.1, 187.5, 188.1; Yield, 17.9%; MS: 542.803 ([M + H]+); Found, C, 68.73; H, 6.50; Calcd. [C31H35N5O4]+, C, 68.74; H, 6.51; 2,9-Dihydroxy-7-methyl-4,6,6a,7,8,9-hexahydro-indolo[4,3f–g]quinoline9-carboxylic acid [1-(2-hydroxy-1-methyl-ethylcarbamoyl)-2-(5methoxy-1H-indol-3-yl)-ethyl]-amide (6): 1H-NMR, d, J: 2.22 (m,

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3H, CH3), 2.61–2.78 (m, 4H), 3.15 (m, 1H), 3.57 (s, 2H, OCH3), 4.10 (s, 3H); 4.95 (s, 2H), 4.70–5.34 (m, 3H), 7.01 (d, 1H, J = 8.1), 7.65 (t, 1H, J = 8.0), 7.77 (s, 1H), 7.79 (d, 1H, J = 8.1), 8.09 (s, 1H), 7.75, 8.11, 8.17 (s, 3H), 9.55 (d, 1H, J = 1.8), 9.50 (d, 1H, J = 1.6), 10.1, 10.3 (s, 2H); 13CNMR, d, 33.3, 35.7, 35.9, 38.2, 44.9, 51.2, 55.9, 58.2, 59.9, 63.1, 63.8, 64.1, 66.9, 107.2, 112.1, 121.9, 123.9, 126.9, 127.7, 128.9, 130.1, 137.4, 144.4, 145.3, 148.1, 150.2, 170.0, 187.2, 188.0; Yield, 11.0%; MS: 574.661 ([M + H]+); Found, C, 64.90; H, 6.13; Calcd. [C31H35 N5O6]+, C, 64.91; H, 6.15; 9-Hydroxy-2-methoxy-7-methyl-4,6,6a,7, 8,9-hexahydro-indolo[4,3f–g]quinoline-9-carboxylic acid [1-(2-hydroxy-1-methyl-ethylcarbamoyl)-2-(1H-indol-3-yl)-ethyl]-amide (7): 1H-NMR, d, J: 2.17 (m, 3H, CH3), 2.60–2.80 (m, 4H), 3.18 (m, 1H), 3.59 (s, 2H, OCH3), 4.13 (s, 3H); 4.99 (s, 2H), 4.73–5.90 (m, 3H), 7.11 (d, 1H, J = 8.0), 7.66 (t, 1H, J = 8.1), 7.75 (s, 1H), 7.75 (d, 1H, J = 8.0), 8.11 (s, 1H), 7.70, 8.22, 8.28 (s, 3H), 9.59 (d, 1H, J = 1.9), 9.52 (d, 1H, J = 1.7), 10.0, 10.2 (s, 2H); 13C-NMR, d, 33.5, 35.9, 35.8, 38.1, 45.5, 51.5, 55.7, 58.1, 58.9, 62.7, 62.9, 64.6, 65.7, 106.1, 113.6, 122.7, 124.1, 125.8, 125.9, 128.2, 131.0, 137.6, 144.9, 146.9, 149.9, 151.3, 170.6, 187.7, 188.8; Yield, 18.9%; MS: 558.438 ([M + H]+); Found, C, 66.34; H, 6.28; Calcd. [C31H35N5O5]+, C, 66.77; H, 6.33; 9-Hydroxy-2-methoxy-7-methyl-4,6,6a,7,8,9-hexahydro-indolo[4,3f–g] quinoline-9-carboxylic acid [1-(1-hydroxy-propylcarbamoyl)-2(1H-indol-3-yl)-ethyl]-amide (8): 1H-NMR, d, J: 2.26 (m, 3H, CH3), 2.64–2.88 (m, 4H), 3.04 (m, 1H), 3.60 (s, 2H, OCH3), 4.14 (s, 3H); 4.06 (s, 2H), 4.75–5.92 (m, 3H), 7.15 (d, 1H, J = 8.1), 7.55 (t, 1H, J = 8.0), 7.78 (s, 1H), 7.78 (d, 1H, J = 8.5), 8.15 (s, 1H), 7.73, 8.20, 8.30 (s, 3H), 9.63 (d, 1H, J = 2.0), 9.51 (d, 1H, J = 1.8), 10.2, 11.7 (s, 2H); 13C-NMR, d, 33.3, 35.2, 35.7, 38.9, 45.1, 51.0, 55.4, 58.9, 59.7, 62.3, 62.1, 65.8, 65.1, 107.9, 114.2, 123.9, 124.9, 125.1, 125.3, 129.1, 135.2, 138.9, 145.3, 146.0, 150.3, 152.9, 173.5, 188.8, 188.9; Yield, 22.0%; MS: 559.091 ([M + H]+); Found, C, 66.76; H, 6.24; Calcd. [C31H35N5O5]+, C, 66.77; H, 6.33; 3-(1H-Indol-3-yl)-2-[(7-methyl4,6,6a,7,8,9-hexahydro-indolo[4,3-fg]quinoline-9-carbonyl)-amino]propionic acid (9): 1H-NMR, d, J: 4.22 (s, 3H); 4.11 (s, 2H), 4.79–5.90 (m, 5H), 7.14 (d, 1H, J = 8.0), 7.56 (t, 1H, J = 8.0), 7.77 (s, 1H), 7.79 (d, 1H, J = 8.6), 8.22 (s, 1H), 7.75, 8.23, 8.38 (s, 3H), 9.66 (d, 1H, J = 2.3), 9.50 (d, 1H, J = 1.7); 13C-NMR, d, 45.3, 56.0, 55.3–57.8, 62.2, 62.0, 67.2, 65.0, 108.4, 115.1, 125.4, 126.1, 127.4, 129.2, 129.5, 135.0, 138.5, 145.0, 146.3, 150.0, 153.7, 175.6, 189.3, 189.6, 190.3; Yield, 25.6%; MS: 554.533 ([M + H]+); Found, C, 71.50; H, 5.62; Calcd. [C27H25N4O3]+, C, 71.51; H, 5.56; 3-(6-Hydroxy-1H-indol-3-yl)-2-[(2hydroxy-7-methyl-4,6,6a,7,8,9-hexahydro-indolo[4,3-fg]quinoline9-carbonyl)-amino]-propionic acid (10): 1H-NMR, d, J: 4.14 (s, 3H); 4.23 (s, 2H), 4.80–5.85 (m, 5H), 7.22 (d, 1H, J = 8.2), 7.59 (t, 1H, J = 8.0), 7.73 (s, 1H), 7.88 (d, 1H, J = 8.5), 8.27 (s, 1H), 7.72, 8.28, 8.44 (s, 3H), 9.70 (d, 1H, J = 2.3), 9.59 (d, 1H, J = 1.8), 9.87, 10.02 (s, 2H); 13C-NMR, d, 45.1, 56.3, 55.1–57.9, 62.0, 63.2, 68.1, 65.5, 109.1, 117.0, 125.5, 126.6, 127.5, 129.1, 129.3, 135.0, 138.1, 145.3, 148.2, 150.4, 153.2, 175.9, 190.2, 190.7, 191.3; Yield, 25.6%; MS: 487.509 ([M + H]+); Found, C, 66.72; H, 5.13; Calcd. [C27H25N4O5]+, C, 66.79; H, 5.19; 2-[(2,9-Dihydroxy-7-methyl-4,6,6a,7,8,9-hexahydro-indolo[4,3-fg]quinoline-9-carbonyl)-amino]-3-(6-hydroxy-1H-indol-3yl)-propionic acid (11): 1H-NMR, d, J: 4.17–4.27 (m, 4H); 4.80–5.78 (m, 3H), 7.20 (d, 1H, J = 8.1), 7.56 (t, 1H, J = 8.0), 7.75 (s, 1H), 7.90 (d, 1H, J = 8.5), 8.30 (s, 1H), 7.74, 8.30, 8.50 (s, 3H), 9.72 (d, 1H, J = 2.2), 9.60 (d, 1H, J = 1.8), 9.90, 10.01 (s, 2H); 13C-NMR, d, 45.4, 56.1, 55.0–59.2, 62.3, 65.8, 68.1, 65.3, 110.6, 118.5, 126.3, 126.1, 129.3, 130.7, 133.6, 136.2, 140.8, 145.2, 148.0, 152.4, 157.1, 178.6, 190.1, 192.4, 195.8; Yield, 20.7%; MS: 503.510 ([M+H]+); Found, C, 66.60; H, 5.00; Calcd. [C27H25N4O6]+, C, 66.64; H, 5.02; 4-[(7-Methyl-4,6,6a,7,8,9hexahydro-indolo[4,3-fg]quinoline-9-carbonyl)-amino]-cyclohexanecarboxylic acid (12): 1H-NMR, d, J: 2.54–3.05 (m, 8H, 4  CH2), 3.35 (m, H), 3.89 (m, H), 4.99 (s, 2H), 6.71 (d, 1H, J = 8.0), 7.50 (t, 1H, J = 8.0), 7.64 (s, 1H), 7.80 (d, 1H, J = 8.1), 8.00 (s, 1H), 9.40 (d, 1H, J = 1.6), 9.41 (d, 1H, J = 1.6), 10.08 (s, 1H); 13C-NMR: 4.12, 4.43,

4.57, 4.60, 10.4, 12.3, 55.2, 105.3, 111.5, 120.5, 120.9, 122.9, 124.0, 126.5, 130.1, 137.3, 141.0, 146.5, 179.4, 165.8, 150.5, 152.7, 179.6; Yield, 38.1%; MS: 340.408 ([M + H]+); Found, C, 70.20; H, 6.87; Calcd. [C23H27N3O3]+, C, 70.21; H, 6.92; 4-[(2-Hydroxy-7-methyl4,6,6a,7,8,9-hexahydro-indolo[4,3-fg]quinoline-9-carbonyl)-amino]cyclohexanecarboxylic acid (13): 1H-NMR, d, J: 2.55–3.08 (m, 8H, 4  CH2), 3.37 (m, H), 3.90 (m, H), 5.00 (s, 2H), 6.70 (d, 1H, J = 8.0), 7.52 (t, 1H, J = 8.0), 7.66 (s, 1H), 7.81 (d, 1H, J = 8.0), 7.79 (s, 1H), 9.44 (d, 1H, J = 1.5), 9.40 (d, 1H, J = 1.7), 10.04, 10.18 (s, 2H); 13CNMR: 4.1, 4.7, 4.9, 4.6, 11.8, 12.2, 55.2, 109.4, 110.3, 122.8, 123.2, 123.8, 124.3, 127.2, 132.5, 138.5, 141.1, 147.9, 180.5, 165.9, 155.8, 154.1, 180.5; Yield, 37.5%; MS: 411.335 ([M + H]+); Found, C, 67.31; H, 6.52; Calcd. [C23H27N3O4]+, C, 67.46; H, 6.65; 4[(9-Hydroxy-7-methyl-4,6,6a,7,8,9-hexahydro-indolo[4,3-fg]quinoline-9-carbonyl)-amino]-cyclohexanecarboxylic acid (14): 1HNMR, d, J: 2.55–3.45 (m, 8H, 4  CH2), 3.60 (m, H), 3.94 (m, H), 5.11 (s, 2H), 6.74 (d, 1H, J = 8.1), 7.58 (t, 1H, J = 8.0), 8.03 (s, 1H), 8.84 (d, 1H, J = 8.1), 7.75 (s, 1H), 9.41 (d, 1H, J = 1.9), 9.43 (d, 1H, J = 1.8), 10.02, 11.07 (s, 2H); 13C-NMR: 4.0, 4.6, 5.3, 5.4, 10.4, 11.6, 55.0, 110.3, 111.9, 123.5, 123.0, 125.1, 127.4, 129.3, 135.8, 139.6, 145.0, 150.2, 154.9, 165.0, 157.5, 158.1, 181.2; Yield, 33.2%; MS: 411.335 ([M + H]+); Found, C, 67.18; H, 6.58; Calcd. [C23H27N3O4]+, C, 67.46; H, 6.65; 4-[(2,9-Dihydroxy-7-methyl-4,6,6a,7,8,9-hexahydro-indolo[4,3-fg]quinoline-9-carbonyl)-amino]-cyclohexanecarboxylic acid (15): 1H-NMR, d, J: 2.55–3.33 (m, 8H, 4  CH2), 3.58 (m, H), 3.91 (m, H), 5.10 (s, 2H), 6.76 (d, 1H, J = 8.0), 7.70 (t, 1H, J = 8.3), 8.01 (s, 1H), 8.88 (d, 1H, J = 8.0), 7.80 (s, 1H), 9.40 (d, 1H, J = 1.8), 9.59 (d, 1H, J = 1.8), 10.00, 10.13, 11.43 (s, 3H); 13C-NMR: 4.2, 4.7, 5.1, 5.5, 10.1, 11.3, 55.4, 111.1, 111.7, 125.1, 125.6, 126.8, 127.2, 130.4, 133.2, 140.5, 146.3, 151.3, 155.8, 166.2, 158.7, 159.3, 182.9; Yield, 26.1%; MS: 427.110 ([M+H]+); Found, C, 64.90; H, 6.38; Calcd. [C23H27N3O5]+, C, 64.93; H, 6.40.

5. Physical methods HPLC-ESI-MS/MS measurements were made using TSQ 7000 instrument (Thermo Fisher Inc., Rockville, MD, USA). Two mobile phase compositions were used: (A) 0.1% v/v aqueous HCOOH and (B) 0.1% v/v HCOOH in CH3CN. A triple quadrupole mass spectrometer (TSQ 7000 Thermo Electron, Dreieich, Germany) equipped with an ESI two source was used and operated at the following conditions: capillary temperature 180 °C; sheath gas 60 psi, corona 4.5 lA and spray voltage 4.5 kV. Sample was dissolved in acetonitrile (1 mg/mL) and was injected in the ion source by an autosampler (Surveyor) with a flow of pure acetonitrile (0.2 mL/min). Data processing was performed by Excalibur 1.4 software. A standard LTQ Orbitrap XL (Thermo Fisher Inc.) instrument was used for MALDI-MS measurements, using the UV laser source at 337 nm. An overall mass range of m/z 100–1000 was scanned simultaneously in the Orbitrap analyzer. The ImageQuest 1.0.1 program package was used. The laser energy values were within 12.0– 17.0 lJ. The numbers of averaged laser shots lies within 39–93, the MALDI flow rate values were within 21.3–24.6; the acquisition time was within 30.0–135.1 min, the corresponding elapsed scan time range lies within 18.3–3.55 s, respectively. Chromatographic confirmation about the purity of the studied compounds was performed with a Gynkotek (Germering, Germany) HPLC instrument, equipped with a preparative Kromasil 100 C18 column (250  20 mm, 7 lm; Eka Chemicals, Bohus, Sweden) and a UV detector set at 250 nm. The mobile phase was acetonitrile:water (90:10, v/v) at a flow rate of 4 mL/min. The analytical HPLC was performed on a Phenomenex (Torrance, CA, USA) RP-18 column (Jupiter 300, 150 mm  2 mm, 3 lm) under the same chromatographic conditions as above. The QA was performed on a Shimadzu UFLC XR (Kyoto, Japan) instrument,

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equipped with an auto sampler, PDA, an on-line degasser and column thermostat. As stationary phase a Phenomenex Luna Phenyl– Hexyl column (150 mm  3 mm i.d., 3 lm particle size) was used. The mobile phase consisted of 0.02% (v/v) TFA in water (solvent A) and acetonitrilemethanol 75:25 (v/v; solvent B). Separation was achieved by a gradient analysis starting with 55A–45B, increasing the amount of solvent B in 30 min to 75% and 30.1 min to 100% B, stop time 40 min. For equilibration a post time of 15 min was applied. Other parameters: flow rate 0.30 ml/min, injection volume 5 ll, detection wavelength 280 nm; column temperature 35 °C. NMR spectroscopy was performed with a Varian (Palo Alto, CA, USA) Inova 600, a 600 MHz instrument, with anhydrous DMSO-D6 used as solvent. The NMR spectra were recorded in one-(1D) and two dimensional (2D) modes. 1D mode involved recording 1H and 13C APT spectra. 2D-NMR techniques included correlation spectroscopy (COSY), heteronuclear multibond correlation (HMBC), and heteronuclear single quantum coherence (HSQC). COSY was performed to investigate the coupling of two protons. HMBC reflects long-range CH correlation over two or three bonds, whereas HSQC establishes direct CH correlation. Chromatographic purification was performed with a Gynkotek (Germering, Germany) The UV–VIS–NIR spectra within 200-800 nm, using solvent acetonitrile (Uvasol, Merck product) at a concentration of 2.5.10 5 M in 0.921 cm quartz cells, were recorded on Tecan Safire Absorbance/Fluorescence XFluor 4 V 4.40 spectrophotometer. The CD spectra were measured on JASCO J-715 polarimeter with 0.5 nm resolution. 5.1. Quantum chemical calculations [11] Quantum chemical calculations were performed with GAUSSIAN 09 and Dalton 2.0 program packages [11a,11b]. The geometries of the studied species were preoptimised employing B3LYP [11c] method, CAM-B3LYP [11d], M06-2X functionals [11e,11f,11g]. Molecular geometries were fully optimised by the force gradient method using Bernys’ algorithm. For every structure the stationary points found on the molecule potential energy hypersurfaces were characterised using standard analytical harmonic vibrational analysis. The absence of the imaginary frequencies, as well as of negative eigenvalues of the second-derivative matrix, confirmed that the stationary points correspond to minima of the potential energy hypersurfaces. The calculation of vibrational frequencies and infrared intensities were checked to establish, which kind of performed calculations agree best with the experimental data. The calculations of the molecular vibrations were utilized by the 6-31+G(d,p) and large ‘‘correlation consistent’’ basis sets aug-ccpVDZ and aug-cc-pVTZ (augmented correlation-consistent polarized valence double and triple zeta levels) [11h–11r]. The obtained vibrational characteristics, by the preliminary optimisation of the molecular geometry are correlated to those, obtained by the crystallographic inputs according the method described in. The UV–VIS spectra are calculated, using TDDFT method as above levels and PCM (respectively IPCM) approach. To describe the species in aqueous solution we used both an explicit super molecule and micro hydration approach, in which several water molecules are coordinated to the solute at the optimised geometry of the super molecule, and a polarizable continuum approach. The geometries of all the super molecules in the present study were obtained by a similar approach, but utilizing the polarized SBK basis set at the MP2 level. The geometries have been verified to be local energy minima by frequency analysis, but are not necessarily the global minima. These species were in fact approximations to the real hydrated species. We have not systematically studied the effect of varying the number of water molecules in the super molecule, although we have employed a very large super molecule

29

[5e,5f,5g,11j,11q,11r,11w,11x]. Generally better results are obtained for solutes in aqueous environments if the solute is immersed in a polarizable continuum. For the most recent application of such an approach to spectral properties. It is also possible to use a ‘‘mixed’’ approach, employing both micro hydration and a polarizable continuum. However, many of the studies done so far with this approach have limited the number of water molecules, usually employing only one or two coordinated to the chromophoric group of the molecule. We have tried to approach the problem in a fairly simple yet systematic manner, using several waters of hydration in the micro hydrated species and then immersing this species in a polarizable continuum. We have utilized primarily the COSMO or CPCM version of the polarizable continuum model, although we have also tested the computationally less stable isodensity polarized continuum model. The COSMO solvation approach has been applied both to bare anionic solutes and to the micro hydrated species. For the very largest species considered, we have employed the ONIOM method, in which different parts of the super molecule can be treated at different levels of accuracy, using different basis sets or even different quantum methods. Molecular mechanics calculations were performed, using consequently AMBER, DREIDING and UFF force fields. The crystallographic coordinates for the receptors were obtained from the Protein Databank and were used as input parameters [11z,11aa,11bb,11cc,11dd]. The preoptimised geometry at DFT levels of each of the alkaloids as well as their protonated forms was used [5e,5f,5g,11j,11q,11r,11w,11x]. The charges were assigned to atoms using the DFT calculations and NBO values [5e,5f,5g,11j,11q,11r,11w,11x]. The non-bonded interactions are evaluated for every possible pair of atoms, including the solvent interactions by ONIOM method applying the solvent mixed approach. The interactions between pairs of atoms, separated by three bonds are scaled down. First, were calculated the interactions between all pairs, without taking the scaling into account, than the data set is subtract out the contributions that should have been scaled. 5.2. Statistical and mathematical (Chemometrics) methods [12] The experimental and theoretical spectroscopic patterns were processed by R4Cal Open Office STATISTICs for Windows 7 program package. Baseline correction and curve-fitting procedures were applied according the complex methodology described in [12]. The statistical significance of each regression coefficient was checked by the use of t-test. The model fit was determined by Ftest. The CD spectra were procedure using the derivative analysis and the integration of the spectroscopic patterns as shown in the Fig. 2. The obtained quantities were summarised in the Table 1. The first and second derivative analysis (Fig. 2) as well as the integration was employed for the obtaining of the band positions and the areas giving the De values in the Table 1. The obtained quantities were evaluated statistically after the three repeated measurements and three consequently application of the mathematical procedures. It is important to note that the obtained quantitative data about the both positions of the bands as well as the De were carried out taking into account the experimental signal-to noise ratio obtained using the reference sample as shown in Fig. 2. This procedure appeared especially important for the precise evaluation of the experimental CD spectra, appeared a source of the additional errors, comparing the obtained quantities depending of the conditions and the theoretically predicted rotatory strengths. This evaluation of the experimental dataset appeared crucial for the substances characterizing with the small optical rotation, which would find often amount the different classes of NPs [5]. Notably, special attention need the cases when the CD bands were not completely positive (negative resp.) such for example the band at about

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240 nm in (12). In such cases would apply two different approaches: (i) application of the baseline correction and non-linear curve fitting, defining the bands positions and the areas or (ii) direct application of the non-linear curve fitting, where the positive and negative quantities were summarised (Fig. 2). As could be seen from the data in Fig. 2c and d, the first approach give more accurate result accounting the r2 values.

[3]

[4]

6. Conclusion The paper highlighted the functionalized Ergot-alkaloids as source of the potential psychoactive substances for the treatment the CNS disorders, including controlling/treatment the Schizophrenia. Since, the molecular modelling study of the novel derivatives indicated the high affinity to the serotonin, dopamine and adrenorezeptors, the successfully isolated alkaloids created a formidable challenge for: (a) further molecular drugs-design of the medications with aimed physiochemical properties. Of crucial importance at this stage of the study was the fundamental aspects and understanding the mechanism of biological activity the psychedelics, and in particular those structure–active relationships between the drugs and the receptors, hypothesized and involved in the mechanisms associated the Schizophrenia; (b) providing marked results from the in vivo screening tests, since they were obtained by the become routine synthetic methods; (c) serious potential for practical manufacturing, including the further optimisation the synthetic pathways; (d) development of the analytical protocols for qualitative and quantitative analysis by suitable structural modifications, which perturbed similarities of the physical properties among the homologous series defined by the ergoline skeleton of these derivatives, complicating significantly their analysis especially in mixtures, including unknown natural extracts, and more.

[5]

[6]

[7]

Acknowledgments The authors thank the Deutscher Akademischer Austausch Dienst (DAAD), the Deutsche Forschungsgemeinschaft (DFG), the central instrumental laboratories for structural analysis at Dortmund University (Germany) and the analytical and computational laboratory clusters at the Institute of Environmental Research (INFU) at the same University. References [1] (a) R. Hruska, E. Silbergeld, J. Neurosci. Res. 6 (1981) 1; (b) J. Cheng, C. Coyle, D. Panaccione, S. O’Connor, J. Am. Chem. Soc. 132 (2010) 12835; (c) P. Stadler, R. Giger, in: P. Krosgard-Larson, H. Kofod (Eds.), Natural Products and Drug Development, Munksgaard, Copenhagen, Denmark, 1984, pp. 463– 485; (d) A. Burkhalter, D. Julius, B. Katzung, in: B. Katzung (Ed.), Basic and Clinical Pharmacology, Appleton-Lange, New York, 1998, pp. 261–286,; (e) B. Berde, E. Stuermer, in: W. Aellig, B. Berde, O. Schild (Eds.), Introduction to the Pharmacology of Ergot Alkaloids and Related Compounds, Springer, Berlin, 1978, pp. 1–28; (f) I. Ortel, U. Keller, J. Biological Chem. 284 (2009) 6650; (g) C. Wallwey, S. Li, Nat. Prod. Rep. 28 (2011) 496; (h) J. Cheng, C. Coyle, D. Panaccione, S. O’Connor, J. Am. Chem. Soc. 132 (2010) 1776; (i) A. Zhang, J. Neumeyer, R. Baldessarini, Chem. Rev. 107 (2007) 274; (j) R. Markstein, M. Seiler, A. Jaton, U. Briner, Neurochem. Int. 20 (1992) 211S. [2] (a) C. Schoning, M. Flieger, H. Pertz, J. Anim. Sci. 79 (2001) 2202; (b) D. Dyer, Life Sci. 53 (1993) 223; (c) H. Pertz, H. Milhahn, E. Eich, J. Med. Chem. 42 (1999) 659; (d) E. Müller-Schweinitzer, Gen. Pharmacol. 14 (1983) 95; (e) D. Silberstein, Headache 37 (1997) S15; (f) E. Jacoby, R. Bouhelal, M. Gerspacher, K. Seuwen, ChemMedChem 1 (2006) 760; (g) F. Fanelli, P. De Benedetti, Chem. Rev. 111 (2011) PR438; (h) D. Nichols, C. Nichols, Chem. Rev. 108 (2008) 1614; (i) L. Valdivia, D. Centurión, U. Arulmani, P. Saxena, C. Villalón, Naunyn-

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