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A CoMFA study of histamine H3 receptor agonists
Relating
to Invited
Lecture 3 & &Pharmacology
(,)htMrPn~~.Fm.UnmvUt~“n. [email protected] ,3)U”,,(, de Nuro~*
The histamine Hs-receptor proved to act as presynaptic autoand heteroreceptor influencing the release of a number of different neurotransmitters in the central nervous system as well as in the periphery. Starting from the highly potent and selective Hs-receptor agonist (R)-a-methylhistamine we developed azomethine derivatives with 2-hydroxybenzophenone and related derivatives in order to modify the physicochemical properties for improved phannacokinetic effects (Krause et al., 1995). /--7 Deoendina on thd substirution pattern of the pro-moiety it is possible to n target the drug P&W on peripheral or central tissues with improved bioavailability. These novel prodrugs are no longer substrates for histamine methyltransferase which is the most important inactivating enzyme in man (Garbarg et al., 1991). Investigations on the parent prodrug showed promising antiinflammatory and antinociceptive properties in rodents. First studies in healthy human volunteers proved high plasma levels of the active drug for a prolonged duration after oral administration. Therefore, these azomethine prodrugs seem to be promising therapeutics for inflammatory diseases and a novel antinociceptive approach. Garbarg. M.. Arrang. J.-M..Schunack. W.. Lipp.R..Stark.Ii.. Lecomte,J.-M..and Schwartz.J.-C.0991). PCT Int. Aool. WO 91117 146 114.11.19911. Krause, M.. Rouleab. A..Stark.l-l.. Luger.P..Lipp.R.,G&q. M., &hwa@ J.-C., and Schunack.W.(1995). J.Med.Chem. 39.4070-4079. SupportedbytheSiomedlcal8
Heaith ResearchProgrammeoftheEuropean
the activity receptor.
and
~.~95BMn,Gnm~~~B-~.o*woMrr**~~ INSERM ,“mw *t.
et munucdogl..
Pw!I. FIw.z?
H&eceptor antagonists stimulate the release of histamine from histaminergic neurons via presynaptic H3-autoreceptors (Arrang et al., 1967). Acting on histamine Ha-heteroreceptors they also modulate the release of different neurotransmitters (Schlicker et al., 1994). New leads of histamine H+eceptor antagonists were developed according to a previously described general construction pattern (Lipp et al., 1992). The novel histamine Ha-receptor R’ antagonists contain a 3-(1 Kimidazol-4yl)propyl diphenylmethyl ether structure with different substitution pattern. On C synaptosomes of rat cerebral cortex these compounds show good activity in vitro (-log & 6.7-7.6) and in mice brain (F :I Rz after p.o. administration high activity in % vivo (EDm up to 1 .l mgIkg). The in vitro activity at HI- and Hz-receptor subtypes was also investigated. Although the activity of ethers is at least 30 times lower at Hz-receptors than at Hs-receptors, pronounced H,-receptor antagonist activity has been found (-log Ks up to 7.1). This activity might be explained by their structural similarity to classical HI-receptor antagonists, e.g. diphenhydramine. The novel ether derivatives are highly active ligands in vivo displaying a new combined H&H,-receptor antagonist profile. Arrang.J.-M.etal.(1987).Nature(London)327. 117-123. Schlicker. E. etal.(1994),Fundam.Ciin. Phannacol.8. 128-137. Llpp.R. et al.(1992).In Schwartz,J.-C..Haas, H. L. (eds.). The Histamine Receptor. Ser.ReceptorBiochemcstryandMethodology.Vol16.WileyUss,N.Y.,pp.57-72. Supported by the Siomedlcal8 Health Research Programme
of the European Union.
Union.
The histamine H receptor agonists are known to inhibit the and other synthesis of hl2 tamine and the release of histamine neurotransmitters in the central nervous system and in peripheral organs. In this study we used Comparative Molecular Field Analysis (COMFA) to verify the structural features of H receptor agonists which are essential for a possible mode of activation of the
Sl17
& Drug Receptors (P1.079-Pl.100)
tasuggest
(pD values 3 Molecular structures of 37 H3 receptor agonist 9.5) were made and minimized us,ng Sybyl software force P Tnpos field) and the atomic point charges were calculated with a semi-empirical AM1 method. The imidazole ring and the protonable nitrogen of the side chain of the compounds were superSteric and electrostatic fields were used in CoMFA. imposed. Ty improve preliminary results the field fit alignment and q -validated region selection were carried out. Statistics of the final CoMFA were: q* = 0.561. r* = 0.947, SPRESS = 1.159 and the optimum number of components was 5. No outliers were detected. Accord.ing to CoMFA steric and electrostatic properties close to the imidazole ring and the protonable nitrogen of the side chain are important for the agonist In low energy conformations of each histamine H3, activity. receptor agonist an intramolecular hydrogen bond formation 1s possible. This may initiate proton transfer and further activation of the reseptor.
Lansoprazole represent one of the relatively new compound from the group of antiulcer drugs acting at the final enzymatic step of the acid secretory paiJway of the parietal cell, decreasing gastric acid secretion regardless of the primary stimulus The main obstacle in preparing an effective la~~prazolc peroral formulation represents its unstability, specially in the solutions with lower pH values. Additionally, probably because of its unstability, no physicochemical data (i.e. pKa, aqueous solubility, partition coefficient) are available in the literature Therefore our intenhon war, lo deternke some of physicochemical parameters with the aim to get alI the necessary information for design of peroral formulation. Fii of all we determined the lansoprazcile stability in aqusolutions with different pH values @H = 1to pH = 13) It was found that lansoprazole decomposes in acidx solutions (pH
to Invited
Lecture 3 & &Pharmacology
(,)htMrPn~~.Fm.UnmvUt~“n. [email protected] ,3)U”,,(, de Nuro~*
The histamine Hs-receptor proved to act as presynaptic autoand heteroreceptor influencing the release of a number of different neurotransmitters in the central nervous system as well as in the periphery. Starting from the highly potent and selective Hs-receptor agonist (R)-a-methylhistamine we developed azomethine derivatives with 2-hydroxybenzophenone and related derivatives in order to modify the physicochemical properties for improved phannacokinetic effects (Krause et al., 1995). /--7 Deoendina on thd substirution pattern of the pro-moiety it is possible to n target the drug P&W on peripheral or central tissues with improved bioavailability. These novel prodrugs are no longer substrates for histamine methyltransferase which is the most important inactivating enzyme in man (Garbarg et al., 1991). Investigations on the parent prodrug showed promising antiinflammatory and antinociceptive properties in rodents. First studies in healthy human volunteers proved high plasma levels of the active drug for a prolonged duration after oral administration. Therefore, these azomethine prodrugs seem to be promising therapeutics for inflammatory diseases and a novel antinociceptive approach. Garbarg. M.. Arrang. J.-M..Schunack. W.. Lipp.R..Stark.Ii.. Lecomte,J.-M..and Schwartz.J.-C.0991). PCT Int. Aool. WO 91117 146 114.11.19911. Krause, M.. Rouleab. A..Stark.l-l.. Luger.P..Lipp.R.,G&q. M., &hwa@ J.-C., and Schunack.W.(1995). J.Med.Chem. 39.4070-4079. SupportedbytheSiomedlcal8
Heaith ResearchProgrammeoftheEuropean
the activity receptor.
and
~.~95BMn,Gnm~~~B-~.o*woMrr**~~ INSERM ,“mw *t.
et munucdogl..
Pw!I. FIw.z?
H&eceptor antagonists stimulate the release of histamine from histaminergic neurons via presynaptic H3-autoreceptors (Arrang et al., 1967). Acting on histamine Ha-heteroreceptors they also modulate the release of different neurotransmitters (Schlicker et al., 1994). New leads of histamine H+eceptor antagonists were developed according to a previously described general construction pattern (Lipp et al., 1992). The novel histamine Ha-receptor R’ antagonists contain a 3-(1 Kimidazol-4yl)propyl diphenylmethyl ether structure with different substitution pattern. On C synaptosomes of rat cerebral cortex these compounds show good activity in vitro (-log & 6.7-7.6) and in mice brain (F :I Rz after p.o. administration high activity in % vivo (EDm up to 1 .l mgIkg). The in vitro activity at HI- and Hz-receptor subtypes was also investigated. Although the activity of ethers is at least 30 times lower at Hz-receptors than at Hs-receptors, pronounced H,-receptor antagonist activity has been found (-log Ks up to 7.1). This activity might be explained by their structural similarity to classical HI-receptor antagonists, e.g. diphenhydramine. The novel ether derivatives are highly active ligands in vivo displaying a new combined H&H,-receptor antagonist profile. Arrang.J.-M.etal.(1987).Nature(London)327. 117-123. Schlicker. E. etal.(1994),Fundam.Ciin. Phannacol.8. 128-137. Llpp.R. et al.(1992).In Schwartz,J.-C..Haas, H. L. (eds.). The Histamine Receptor. Ser.ReceptorBiochemcstryandMethodology.Vol16.WileyUss,N.Y.,pp.57-72. Supported by the Siomedlcal8 Health Research Programme
of the European Union.
Union.
The histamine H receptor agonists are known to inhibit the and other synthesis of hl2 tamine and the release of histamine neurotransmitters in the central nervous system and in peripheral organs. In this study we used Comparative Molecular Field Analysis (COMFA) to verify the structural features of H receptor agonists which are essential for a possible mode of activation of the
Sl17
& Drug Receptors (P1.079-Pl.100)
tasuggest
(pD values 3 Molecular structures of 37 H3 receptor agonist 9.5) were made and minimized us,ng Sybyl software force P Tnpos field) and the atomic point charges were calculated with a semi-empirical AM1 method. The imidazole ring and the protonable nitrogen of the side chain of the compounds were superSteric and electrostatic fields were used in CoMFA. imposed. Ty improve preliminary results the field fit alignment and q -validated region selection were carried out. Statistics of the final CoMFA were: q* = 0.561. r* = 0.947, SPRESS = 1.159 and the optimum number of components was 5. No outliers were detected. Accord.ing to CoMFA steric and electrostatic properties close to the imidazole ring and the protonable nitrogen of the side chain are important for the agonist In low energy conformations of each histamine H3, activity. receptor agonist an intramolecular hydrogen bond formation 1s possible. This may initiate proton transfer and further activation of the reseptor.
Lansoprazole represent one of the relatively new compound from the group of antiulcer drugs acting at the final enzymatic step of the acid secretory paiJway of the parietal cell, decreasing gastric acid secretion regardless of the primary stimulus The main obstacle in preparing an effective la~~prazolc peroral formulation represents its unstability, specially in the solutions with lower pH values. Additionally, probably because of its unstability, no physicochemical data (i.e. pKa, aqueous solubility, partition coefficient) are available in the literature Therefore our intenhon war, lo deternke some of physicochemical parameters with the aim to get alI the necessary information for design of peroral formulation. Fii of all we determined the lansoprazcile stability in aqusolutions with different pH values @H = 1to pH = 13) It was found that lansoprazole decomposes in acidx solutions (pH