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AB initio investigations of local anesthetic-phospholipid model membrane interactions
Journal of Molecular Structure, 104 (1983) THEOCHEM Elsevier Science Publishers B.V., Amsterdam
451-457 -
Printed
AB INITIO INVESTIGATIONS OF LOCAL MODEL MEMBRANE INTERACTIONS
in The Netherlands
ANESTHETIC-PHOSPHOLIPID
M. REMKO Institute of Chemistry, (Czechoslovakia)
Comenius
University,
KalinEiakova
8, 832
32 Bratislava
P. Th. VAN DUIJNEN Theoretical Nijenborgh (Received
Chemistry Group, Laboratory 16, 9 747 AG Groningen (The 21 January
of Chemical Netherlands)
Physics,
University
of Groningen,
1983)
ABSTRACT A “double zeta” basis set ab initio SCF MO method has been used to study intermolecular hydrogen bonding in the systems [trimethylamine-dimethylphosphate monoanion] H’ (I), anilinedimethylphosphate monoanion (II) and formanilide-dimethylphosphate monoanion (III) which represent the models for associative sites of both local anesthetics and the phospholipid part of the nerve membrane. According to our calculations complex bond and an interaction I was found to be the most stable with an N+-H-e * O-hydrogen energy of 580.17 kJ mall’. The proton transfer in I was also investigated. The proton potential function calculated at distance RN.. . 0 = 0.269 nm showed a double-minimum. INTRODUCTION
The molecular mechanism by which local anesthetics reversibly block nerve conduction is still not clearly understood. One view is that local anesthetics act on a protein site of the nervous membrane [l-3]. Other studies have shown that local anesthetics interact specifically with the phosphodiester groups in phospholipids, phosphoproteins, ribonucleic acids and synthetic phosphodiesters [4-g]. The nature of these interactions has been the subject of speculation [4,8--131. Several studies have considered whether the charged or the uncharged form is responsible for the anesthetic effect [9, 12,141. The importance of hydrogen bonds in the interaction of local anesthetics with the receptor in the membrane was first suggested by Sachs and Pletcher [15]. Investigations of model systems [16,17] have shown that local anesthetics can form hydrogen bonds with possible associative sites of the lipoprotein part of the membrane. The X-ray investigations of the procaine dihydrogen orthophosphate [ 181, procaine bis-p-nitrophenyl phosphate [ 191 and lidocaine bis-p-nitrophenyl phosphate [ 201 showed that the local anesthetics in these model complexes interact by means of intermolecular hydrogen bonds with phosphodiester groups of the membrane. 0166-1280/83/$03.00
0 1983
Elsevier
Science
Publishers
B.V.
-
452
In order to conduct a deeper theoretical study of the hydrogen bonds in the local anesthetic-model nerve membrane interactions, ab initio calculations of the hydrogen bonded systems [trimethylamine-dimethylphosphate monoanion] H+ (I), aniline-dimethylphosphate monoanion (II) and formanilide-dimethylphosphate monoanion (III), respectively, were carried out. Aniline, formanilide and trimethylamine represent possible associative sites of the local anesthetics procaine and lidocaine. Dimethylphosphate monoanion represents the associative site of the phospholipid part of the membrane. METHOD OF CALCULATION
For the calculations of the interaction energies and the electronic structure of the hydrogen bonded complexes investigated (Fig. l), the ab initio molecular orbital method has been used. The gaussian basis set used was that of Roos and Siegbahn [21] contracted to a “double zeta” atomic basis [22]. The input geometry was derived from the X-ray data for procaine [ 18, 191, lidocaine [ 201, trimethylamine [23] and dimethylphosphate monoanion [24]. In order to find the relative stability of the systems investigated a restricted optimization was performed, in which only the length RN_-H was determined. The interaction energy, AE, was evaluated at the fixed experimental values of the Ro.. . N distances taken from X-ray determinations of lidocaine bis-p-nitrophenylphosphate [ 201 and procaine bis-p-nitrophenylphosphate [ 191. AE was defined as the difference between the total energy of complex and total energy of the isolated monomers. AE = E(R)
- E(Rw)
(1)
The proton affinities of the trimethylamine and dimethylphosphate monoanion were also calculated. The proton affinity of the base B is the negative AEr value for the exothermic reaction. B + H+ + BH’
(2)
AEr is given by the energy difference
between
the B and BH’ species
AE,=E,-EE,,+
(3)
where E, is the energy of the base,
H OCH,
OCH,
CH3
H
I H&O-P-O
H&O-
-----H----N--CH,
P -0
‘CN,
OCH, I H&o-p-o-----H-N
-----H--l:
/
I
b
CH, I
b
b
b II
Fig. 1. Molecular arrangement of the complexes studied.
nt
453
The calculations were performed on a CDC Cyber 170/760 using a program system [ 251 specially designed for calculations on large, non-symmetric molecules. RESULTS AND DISCUSSION
At physiological values of pH the phosphate group of the phospholipids bears a negative charge [ 26, 271. Similarly in physiological solutions of neutral pH the amino groups of various local anesthetics are partially ionized and thus both cationic and uncharged forms are present [9,14,28]. The interaction of the negatively charged phosphate group of the phospholipids with polar proton donor groups of various local anesthetics can represent one of the possible types of drug-receptor interaction [4, 291. We studied this type of interaction on model systems [ trimethylamine-dimethylphosphate monoanion] H+ (I), anilinedimethylphosphate monoanion (II) and formanilide-dimethylphosphate monoanion (III) respectively. Table 1 gives the geometry and interaction energy of these systems. The hydrogen bonds are fairly strong because of the negative charge on the phosphate. The phosphodiester group forms the most stable complex with the hydrophilic part of the local anesthetic (modelled by the trimethylamine cation) with an interaction energy of 580.17 kJ mol-‘. Of the two polar proton donor groups corresponding to the hydrophobic part of the drug (-NH? and -NH-CO-) the aniline N-H group forms the stronger hydrogen bond with the dimethylphosphate monoanion. Our model calculations, although corresponding to the vapor phase, thus indicate that, of the local anesthetic polar groups studied, the amino group of the cationic local anesthetic is the most eligible proton donor in interactions between local anesthetics and the phosphate group of phospholipids. Figure 2 presents the results of the calculations of the proton potential function for proton transfer in the N+--Ha - - O- bond of the [trimethylamine-dimethylphosphate monoanion] H+ system. The proton potential curve shows a double-minimum character. The second minimum, corresponding to the neutral N* - * H-O hydrogen bond, was found to be more TABLE 1 Geometries and interaction energies of the systems investigated System
RF?. . N (nm)
REH
I
0.26gb 0.26gb o.295c 0.280b
0.1170 0.1670 0.1016 0.1062
II III
(nm)
AE
(kJ mole’)
580.17* 113.02s 175.39 143.79
‘Values calculated with respect to the global minimum on the proton transfer energy curve. bRef. 20. ‘Ref. 19.
0.10
0.14
0.18 RN-H hd
Fig. 2. Proton potential function for the proton transfer in [trimethylamine-dimethylphosphate monoanion] H+ system (RN. ..0 = 0.269nm). Crosses indicate the NH distances at which the total energy of the systems was calculated.
stable by 22.58 kJ mol-’ than the first one. However, it is well known, from both ab initio [ 30-331 and semi-empirical calculations [ 30, 34-37) that the shape of the proton potential curve depends on both intermolecular conformation and the actual computational method used. Consequently, any method which attempts to describe proton transfer potential functions reasonably well, has to reproduce proton affinities with reasonable accuracy. Accordingly we also computed the proton affinities AEr (eqn. 3) of the trimethylamine and the dimethylphosphate monoanion using the same geometry for the neutral and charged forms (Table 2). The calculated proton affinity, AE,, of trimethylamine was found to be in a very good agreement with the vapor phase experimental proton affinities (Table 2) and therefore it may be concluded that “double zeta” ab initio calculations of AErrepresent closely the intrinsic basicities of the compounds under study. A somewhat higher value of AEr (1023.4 kJ mol-‘) was found [41], also from double zeta ab initio calculations, for the amino nitrogen protonation in the 1[2-(2methoxyphenylcarbamoyl-oxy)ethyl] piperidine, a compound with considerable local anesthetic activity [42] . In Table 3 the charge shifts and charge transfer of the hydrogen bonded atoms are shown. CSN, CSn and CSo represent the charge shifts on hydrogenbonded atoms nitrogen, oxygen and hydrogen respectively, upon hydrogen bond formation. CTrepresents the total charge transfer, i.e. the total number
455 TABLE 2 Proton affinities of trimethylamine Molecule or ion
Reaction
(CW,N
(CH,),N
(CH,M’O;
(CH,),PO;
and the dimethylphosphate
+ H’ -+ (CH,),NH+ + H’ -+ (CH,),PC,H
monoanion
P-‘%p (kJ mol-‘)
RX--H (nm)
944.4b 927.6’
0.117
948.9
0.102
1416.1
-
A& (kJ mol-‘)
aVapor phase values. bRef. 34. ‘Value given in ref. 35 has been corrected relative to the PA for NH, of 846.8 kJ mall’ [ 361.
of electrons lost by the electron donor. According to Table 3 the electron density increases on the hydrogen-bonded oxygen of the dimethylphosphate monoanion in both neutral N. - - H-O and proton transfer N’--H. * * Ohydrogen bonds of the system I. In contrast, very small changes in the electron density of this oxygen were observed in the systems II and III respectively. In all systems the electron density of the nitrogen atoms increases. Hydrogen-bonded hydrogens have a positive character and their electron density is reduced due to the formation of the hydrogen bond. CONCLUSIONS
From this study of the hydrogen bonding properties of the local anesthetic polar groups (modelled by trimethylamine cation, aniline and formanilide) with the phosphodiester group modelling the membrane the following conclusions can be drawn: (1) The phosphate group of the membrane forms the strongest hydrogen bond with the cationic amino group of the local anesthetic, (2) In their interaction with the dimethylphosphate monoanion, aromatic amines act as stronger proton donors than aromatic amides. TABLE 3 Charge shifts and charge transfer* System Ib IC II III
csN
-126 -97 -111 -67
CSH
138 39 132 111
cso
-54 -53 9 -6
CT 199 88 89 118
aNegative CS values mean increasing electron density as compared with the monomers. bValues corresponding to the proton transfer hydrogen bond N+-He * * 0-i CValues corresponding to the neutral hydrogen bond N. - -H-O.
456
(3) The proton transfer investigated in the system [trimethylaminedimethylphosphate monoanion] H” showed a double-minimum character. (4) One of the most important properties of lipids in membranes is their ability to interact via intermolecular hydrogen bonds [ 27, 431. It is therefore probable that local anesthetics, through their hydrogen bonding ability, could act as perturbers of these hydrogen bonds, which eventually leads to conformational changes of the macromolecules forming the membrane and so disturbs the conduction system of the nerve cell. REFERENCES 1 J. L. Denburg, M. E. Eldefrawi and R. O’Brien, Proc. Natl. Acad. Sci. U.S.A., 69 (1972) 177. 2 M. Weber and J. P. Changeux, Mol. Pharmacol., 10 (1974) 35. 3 J. R. Trudell, Anesthesiology, 46 (1977) 5. 4 M. B. Feinstein, J. Gen. Physiol., 48 (1964) 357. 5 M. B. Feinstein and M. Paimre, Biochim. Biophys. Acta, 115 (1966) 33. 6 J. M. Ritchie and P. Greengard, Annu. Rev. Pharmacol., 6 (1966) 405. 7 D. Papahadjopoulos, Biochim. Biophys. Acta, 265 (1972) 169. 8 M. A. Singer and M. K. Jain, Can. J. Biochem., 58 (1980) 815. 9 Y. Boulanger, S. Schreier, L. C. Leitch and I. C. P. Smith, Can. J. Biochem., 58 (1980) 986. 10 M. P. Blaustein and D. E. Goldman, Science, 153 (1966) 429. 11 S. H. Chu, G. R. Hillman and H. G. Mautner, J. Med. Chem., 15 (1972) 760. 12 G. R. Strichatz, J. Gen. Physiol., 62 (1973) 37. 13 H. C. Liu, I. Ueda and H. Eyring, Proc. Natl. Acad. Sci. U.S.A., 73 (1976) 3726. 14 J. C&bon, Biochim. Biophys. Acta, 290 (1972) 51. 15 M. Sax and J. Pletcher, Science, 166 (1969) 1546. 16 M. Guerin, J. M. Dumas and C. Sandorfy, Can. J. Chem., 58 (1980) 2080. 17 M. Remko, V. Frecer and J. CiZmirik, Collect. Czech. Chem. Commun., 48 (1983) 533. 18 R. G. Freeman and Ch. E. Bugg, Acta Crystallogr. Sect. B, 31 (1975) 96. 19 M. Sax, J. Pletcher and B. Gustaffson, Acta Crystallogr. Sect. B, 26 (1970) 114. 20 C. S. Yoo, E. Abola, M. K. Wood, M. Sax and J. Pletcher, Acta Crystallogr. Sect. B, 31 (1975) 1354. 21 B. Roos and P. Siegbahn, Theor. Chim. Acta, 17 (1970) 209. 22 P. Th. van Duijnen, B. T. Thole, R. Broer and W. C. Nieuwpoort, Int. J. Quantum Chem., 17 (1980) 651. 23 L. E. Sutton (Ed.), Tables of Interatomic Distances, Spec. Publ. No 11, The Chemical Society, London, 1958; Configurations in Molecules and Ions, Spec. Publ. No. 18, The Chemical Society, London, 1965. 24 M. D. Newton, J. Am. Chem. Sot., 95 (1973) 256. 25 P. Th. van Duijnen and B. T. Thole, unpublished. 26 C. V. M. Smith, Molecular Biology, Faber and Faber, London, 1968. 27 A. J. Hopfinger, Intermolecular Interactions and Biomolecular Organization, J. Wiley and Sons, New York, 1977. 28 M. A. Singer, Biochem. Pharmacol., 26 (1977) 51. 29 J. Btichi and X. Perlia, in E. J. Arri’ens (Ed.), The Design of Local Anesthetics in Drug Design, Vol. III, Academic Press, New York, 1972. 30 P. Schuster, W. Jakubetz, G. Beier, W. Meyer and B. M. Rode in E. D. Bergman and B. Pullman (Eds.), Chemical and Biochemical Reactivity, D. Reidel, Dordrecht, 1974. 31 E. Clementi, J. Mehl and W. von Niessen, J. Chem. Phys., 54 (1971) 508.
457 32 J. J. Delpuerch, G. Serratrice, A, Strich and A. Weilard, J. Chem. Sot., Chem. Commun., 817 (1972). 33 S. Scheiner, J. Chem. Phys., 75 (1981) 5791 and references therein. 34 S. Scheiner and C. W. Kern, J. Am. Chem. Sot., 101 (1979) 4081. 35 M. Remko, Adv. Mol. Relax. Interaction Processes, 16 (1980) 155. 36 M. Remko and L. Krasnec, Adv. Mol. Relax. Interaction Processes, 18 (1980) 1. 37 M. Remko, Collect. Czech. Chem. Commun., 47 (1982) 1893. 38 R. G. Cave11and D. A. Allison, J. Am. Chem. Sot., 99 (1977) 4203. 39 D. H. Aue, H. M. Webb and M. T. Bowers, J. Am. Chem. Sot., 98 (1976) 311. 40 P. Kebarle, Annu. Rev. Phys. Chem., 28 (1977) 445. 41 M. Remko, I. Sekerka and P. Th. van Duijnen, Arch. Pharm., Weinheim, 316 (1983) in press. 42 J. CiZmlrik, A. Borovansky and P. Svec, Pharmazie, 33 (1978) 297. 43 J. M. Boggs, Can. J. Biochem., 58 (1980) 755.
451-457 -
Printed
AB INITIO INVESTIGATIONS OF LOCAL MODEL MEMBRANE INTERACTIONS
in The Netherlands
ANESTHETIC-PHOSPHOLIPID
M. REMKO Institute of Chemistry, (Czechoslovakia)
Comenius
University,
KalinEiakova
8, 832
32 Bratislava
P. Th. VAN DUIJNEN Theoretical Nijenborgh (Received
Chemistry Group, Laboratory 16, 9 747 AG Groningen (The 21 January
of Chemical Netherlands)
Physics,
University
of Groningen,
1983)
ABSTRACT A “double zeta” basis set ab initio SCF MO method has been used to study intermolecular hydrogen bonding in the systems [trimethylamine-dimethylphosphate monoanion] H’ (I), anilinedimethylphosphate monoanion (II) and formanilide-dimethylphosphate monoanion (III) which represent the models for associative sites of both local anesthetics and the phospholipid part of the nerve membrane. According to our calculations complex bond and an interaction I was found to be the most stable with an N+-H-e * O-hydrogen energy of 580.17 kJ mall’. The proton transfer in I was also investigated. The proton potential function calculated at distance RN.. . 0 = 0.269 nm showed a double-minimum. INTRODUCTION
The molecular mechanism by which local anesthetics reversibly block nerve conduction is still not clearly understood. One view is that local anesthetics act on a protein site of the nervous membrane [l-3]. Other studies have shown that local anesthetics interact specifically with the phosphodiester groups in phospholipids, phosphoproteins, ribonucleic acids and synthetic phosphodiesters [4-g]. The nature of these interactions has been the subject of speculation [4,8--131. Several studies have considered whether the charged or the uncharged form is responsible for the anesthetic effect [9, 12,141. The importance of hydrogen bonds in the interaction of local anesthetics with the receptor in the membrane was first suggested by Sachs and Pletcher [15]. Investigations of model systems [16,17] have shown that local anesthetics can form hydrogen bonds with possible associative sites of the lipoprotein part of the membrane. The X-ray investigations of the procaine dihydrogen orthophosphate [ 181, procaine bis-p-nitrophenyl phosphate [ 191 and lidocaine bis-p-nitrophenyl phosphate [ 201 showed that the local anesthetics in these model complexes interact by means of intermolecular hydrogen bonds with phosphodiester groups of the membrane. 0166-1280/83/$03.00
0 1983
Elsevier
Science
Publishers
B.V.
-
452
In order to conduct a deeper theoretical study of the hydrogen bonds in the local anesthetic-model nerve membrane interactions, ab initio calculations of the hydrogen bonded systems [trimethylamine-dimethylphosphate monoanion] H+ (I), aniline-dimethylphosphate monoanion (II) and formanilide-dimethylphosphate monoanion (III), respectively, were carried out. Aniline, formanilide and trimethylamine represent possible associative sites of the local anesthetics procaine and lidocaine. Dimethylphosphate monoanion represents the associative site of the phospholipid part of the membrane. METHOD OF CALCULATION
For the calculations of the interaction energies and the electronic structure of the hydrogen bonded complexes investigated (Fig. l), the ab initio molecular orbital method has been used. The gaussian basis set used was that of Roos and Siegbahn [21] contracted to a “double zeta” atomic basis [22]. The input geometry was derived from the X-ray data for procaine [ 18, 191, lidocaine [ 201, trimethylamine [23] and dimethylphosphate monoanion [24]. In order to find the relative stability of the systems investigated a restricted optimization was performed, in which only the length RN_-H was determined. The interaction energy, AE, was evaluated at the fixed experimental values of the Ro.. . N distances taken from X-ray determinations of lidocaine bis-p-nitrophenylphosphate [ 201 and procaine bis-p-nitrophenylphosphate [ 191. AE was defined as the difference between the total energy of complex and total energy of the isolated monomers. AE = E(R)
- E(Rw)
(1)
The proton affinities of the trimethylamine and dimethylphosphate monoanion were also calculated. The proton affinity of the base B is the negative AEr value for the exothermic reaction. B + H+ + BH’
(2)
AEr is given by the energy difference
between
the B and BH’ species
AE,=E,-EE,,+
(3)
where E, is the energy of the base,
H OCH,
OCH,
CH3
H
I H&O-P-O
H&O-
-----H----N--CH,
P -0
‘CN,
OCH, I H&o-p-o-----H-N
-----H--l:
/
I
b
CH, I
b
b
b II
Fig. 1. Molecular arrangement of the complexes studied.
nt
453
The calculations were performed on a CDC Cyber 170/760 using a program system [ 251 specially designed for calculations on large, non-symmetric molecules. RESULTS AND DISCUSSION
At physiological values of pH the phosphate group of the phospholipids bears a negative charge [ 26, 271. Similarly in physiological solutions of neutral pH the amino groups of various local anesthetics are partially ionized and thus both cationic and uncharged forms are present [9,14,28]. The interaction of the negatively charged phosphate group of the phospholipids with polar proton donor groups of various local anesthetics can represent one of the possible types of drug-receptor interaction [4, 291. We studied this type of interaction on model systems [ trimethylamine-dimethylphosphate monoanion] H+ (I), anilinedimethylphosphate monoanion (II) and formanilide-dimethylphosphate monoanion (III) respectively. Table 1 gives the geometry and interaction energy of these systems. The hydrogen bonds are fairly strong because of the negative charge on the phosphate. The phosphodiester group forms the most stable complex with the hydrophilic part of the local anesthetic (modelled by the trimethylamine cation) with an interaction energy of 580.17 kJ mol-‘. Of the two polar proton donor groups corresponding to the hydrophobic part of the drug (-NH? and -NH-CO-) the aniline N-H group forms the stronger hydrogen bond with the dimethylphosphate monoanion. Our model calculations, although corresponding to the vapor phase, thus indicate that, of the local anesthetic polar groups studied, the amino group of the cationic local anesthetic is the most eligible proton donor in interactions between local anesthetics and the phosphate group of phospholipids. Figure 2 presents the results of the calculations of the proton potential function for proton transfer in the N+--Ha - - O- bond of the [trimethylamine-dimethylphosphate monoanion] H+ system. The proton potential curve shows a double-minimum character. The second minimum, corresponding to the neutral N* - * H-O hydrogen bond, was found to be more TABLE 1 Geometries and interaction energies of the systems investigated System
RF?. . N (nm)
REH
I
0.26gb 0.26gb o.295c 0.280b
0.1170 0.1670 0.1016 0.1062
II III
(nm)
AE
(kJ mole’)
580.17* 113.02s 175.39 143.79
‘Values calculated with respect to the global minimum on the proton transfer energy curve. bRef. 20. ‘Ref. 19.
0.10
0.14
0.18 RN-H hd
Fig. 2. Proton potential function for the proton transfer in [trimethylamine-dimethylphosphate monoanion] H+ system (RN. ..0 = 0.269nm). Crosses indicate the NH distances at which the total energy of the systems was calculated.
stable by 22.58 kJ mol-’ than the first one. However, it is well known, from both ab initio [ 30-331 and semi-empirical calculations [ 30, 34-37) that the shape of the proton potential curve depends on both intermolecular conformation and the actual computational method used. Consequently, any method which attempts to describe proton transfer potential functions reasonably well, has to reproduce proton affinities with reasonable accuracy. Accordingly we also computed the proton affinities AEr (eqn. 3) of the trimethylamine and the dimethylphosphate monoanion using the same geometry for the neutral and charged forms (Table 2). The calculated proton affinity, AE,, of trimethylamine was found to be in a very good agreement with the vapor phase experimental proton affinities (Table 2) and therefore it may be concluded that “double zeta” ab initio calculations of AErrepresent closely the intrinsic basicities of the compounds under study. A somewhat higher value of AEr (1023.4 kJ mol-‘) was found [41], also from double zeta ab initio calculations, for the amino nitrogen protonation in the 1[2-(2methoxyphenylcarbamoyl-oxy)ethyl] piperidine, a compound with considerable local anesthetic activity [42] . In Table 3 the charge shifts and charge transfer of the hydrogen bonded atoms are shown. CSN, CSn and CSo represent the charge shifts on hydrogenbonded atoms nitrogen, oxygen and hydrogen respectively, upon hydrogen bond formation. CTrepresents the total charge transfer, i.e. the total number
455 TABLE 2 Proton affinities of trimethylamine Molecule or ion
Reaction
(CW,N
(CH,),N
(CH,M’O;
(CH,),PO;
and the dimethylphosphate
+ H’ -+ (CH,),NH+ + H’ -+ (CH,),PC,H
monoanion
P-‘%p (kJ mol-‘)
RX--H (nm)
944.4b 927.6’
0.117
948.9
0.102
1416.1
-
A& (kJ mol-‘)
aVapor phase values. bRef. 34. ‘Value given in ref. 35 has been corrected relative to the PA for NH, of 846.8 kJ mall’ [ 361.
of electrons lost by the electron donor. According to Table 3 the electron density increases on the hydrogen-bonded oxygen of the dimethylphosphate monoanion in both neutral N. - - H-O and proton transfer N’--H. * * Ohydrogen bonds of the system I. In contrast, very small changes in the electron density of this oxygen were observed in the systems II and III respectively. In all systems the electron density of the nitrogen atoms increases. Hydrogen-bonded hydrogens have a positive character and their electron density is reduced due to the formation of the hydrogen bond. CONCLUSIONS
From this study of the hydrogen bonding properties of the local anesthetic polar groups (modelled by trimethylamine cation, aniline and formanilide) with the phosphodiester group modelling the membrane the following conclusions can be drawn: (1) The phosphate group of the membrane forms the strongest hydrogen bond with the cationic amino group of the local anesthetic, (2) In their interaction with the dimethylphosphate monoanion, aromatic amines act as stronger proton donors than aromatic amides. TABLE 3 Charge shifts and charge transfer* System Ib IC II III
csN
-126 -97 -111 -67
CSH
138 39 132 111
cso
-54 -53 9 -6
CT 199 88 89 118
aNegative CS values mean increasing electron density as compared with the monomers. bValues corresponding to the proton transfer hydrogen bond N+-He * * 0-i CValues corresponding to the neutral hydrogen bond N. - -H-O.
456
(3) The proton transfer investigated in the system [trimethylaminedimethylphosphate monoanion] H” showed a double-minimum character. (4) One of the most important properties of lipids in membranes is their ability to interact via intermolecular hydrogen bonds [ 27, 431. It is therefore probable that local anesthetics, through their hydrogen bonding ability, could act as perturbers of these hydrogen bonds, which eventually leads to conformational changes of the macromolecules forming the membrane and so disturbs the conduction system of the nerve cell. REFERENCES 1 J. L. Denburg, M. E. Eldefrawi and R. O’Brien, Proc. Natl. Acad. Sci. U.S.A., 69 (1972) 177. 2 M. Weber and J. P. Changeux, Mol. Pharmacol., 10 (1974) 35. 3 J. R. Trudell, Anesthesiology, 46 (1977) 5. 4 M. B. Feinstein, J. Gen. Physiol., 48 (1964) 357. 5 M. B. Feinstein and M. Paimre, Biochim. Biophys. Acta, 115 (1966) 33. 6 J. M. Ritchie and P. Greengard, Annu. Rev. Pharmacol., 6 (1966) 405. 7 D. Papahadjopoulos, Biochim. Biophys. Acta, 265 (1972) 169. 8 M. A. Singer and M. K. Jain, Can. J. Biochem., 58 (1980) 815. 9 Y. Boulanger, S. Schreier, L. C. Leitch and I. C. P. Smith, Can. J. Biochem., 58 (1980) 986. 10 M. P. Blaustein and D. E. Goldman, Science, 153 (1966) 429. 11 S. H. Chu, G. R. Hillman and H. G. Mautner, J. Med. Chem., 15 (1972) 760. 12 G. R. Strichatz, J. Gen. Physiol., 62 (1973) 37. 13 H. C. Liu, I. Ueda and H. Eyring, Proc. Natl. Acad. Sci. U.S.A., 73 (1976) 3726. 14 J. C&bon, Biochim. Biophys. Acta, 290 (1972) 51. 15 M. Sax and J. Pletcher, Science, 166 (1969) 1546. 16 M. Guerin, J. M. Dumas and C. Sandorfy, Can. J. Chem., 58 (1980) 2080. 17 M. Remko, V. Frecer and J. CiZmirik, Collect. Czech. Chem. Commun., 48 (1983) 533. 18 R. G. Freeman and Ch. E. Bugg, Acta Crystallogr. Sect. B, 31 (1975) 96. 19 M. Sax, J. Pletcher and B. Gustaffson, Acta Crystallogr. Sect. B, 26 (1970) 114. 20 C. S. Yoo, E. Abola, M. K. Wood, M. Sax and J. Pletcher, Acta Crystallogr. Sect. B, 31 (1975) 1354. 21 B. Roos and P. Siegbahn, Theor. Chim. Acta, 17 (1970) 209. 22 P. Th. van Duijnen, B. T. Thole, R. Broer and W. C. Nieuwpoort, Int. J. Quantum Chem., 17 (1980) 651. 23 L. E. Sutton (Ed.), Tables of Interatomic Distances, Spec. Publ. No 11, The Chemical Society, London, 1958; Configurations in Molecules and Ions, Spec. Publ. No. 18, The Chemical Society, London, 1965. 24 M. D. Newton, J. Am. Chem. Sot., 95 (1973) 256. 25 P. Th. van Duijnen and B. T. Thole, unpublished. 26 C. V. M. Smith, Molecular Biology, Faber and Faber, London, 1968. 27 A. J. Hopfinger, Intermolecular Interactions and Biomolecular Organization, J. Wiley and Sons, New York, 1977. 28 M. A. Singer, Biochem. Pharmacol., 26 (1977) 51. 29 J. Btichi and X. Perlia, in E. J. Arri’ens (Ed.), The Design of Local Anesthetics in Drug Design, Vol. III, Academic Press, New York, 1972. 30 P. Schuster, W. Jakubetz, G. Beier, W. Meyer and B. M. Rode in E. D. Bergman and B. Pullman (Eds.), Chemical and Biochemical Reactivity, D. Reidel, Dordrecht, 1974. 31 E. Clementi, J. Mehl and W. von Niessen, J. Chem. Phys., 54 (1971) 508.
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