Acetylcholine-Like Molecular Arrangement in Psychomimetic

Proc. Nat. Acad. Sci. USA Vol. 70, No. 11, pp. 3103-3107, November 1973 Acetylcholine-Like Molecular Arrangement in Psychomimetic Anticholinergic Drugs (cholinergic receptor/acetylcholine/phencyclidine/aminoglycolates) SAUL MAAYANI, HAREL WEINSTEIN*, SASSON COHEN, AND MORDECHAI SOKOLOVSKYt Department of Biochemistry, George S. Wise Center for Life Sciences, Tel-Aviv University, Israel; and * Department of Chemistry, The Technion, Haifa, Israel Communicated by David Nachmansohn, July 10, 1973 ABSTRACT A study of the relation between the established, but which fail to cause the perturbation entailing psychotropic activity and the antagonism to acetylcholine the biological may be expected to exhibit antago- observed for some heterocyclic amino esters and com- response, pounds of the phencyclidine series suggests some common nistic properties. The rationalization of both agonistic and molecular structural requirements for their properties. antagonistic activities on the molecular level should therefore Criteria obtained from quantum mechanical calcula- involve consideration of experimentally determined specific tions of acetylcholine-like molecules indicate that their drug-receptor affinity, as well as an evaluation of the factors molecular reactivity with the cholinergic receptor site follows a certain dynamic interaction pattern. This leading to this interaction. pattern suggests a certain molecular arrangement es- The psychomimetic activity observed for a series of potent sential for the interaction, which is based on the electronic anticholinergic drugs (4) offers the opportunity for a method- properties of the molecules and therefore remains valid ical study of the molecular structural factors involved in for the evaluation of compounds which lack any apparent cholinergic activity. Thus, the changes in basic molecular similarity to acetylcholine. This type ofmolecular arrangement is shown to be shared by both activators and in- structure that cause an attenuation of the activity of the hibitors of the acetylcholine receptor discussed here, thus strong anticholinergic amino esters of glycolic acid (amino- supporting the hypothesis of their binding to a common glycolates) in the central nervous system can be shown to receptor. The differences in biological activity are attrib- interfere also with the requirements for anticholinergic activ- uted to the effect of molecular structural factors which ity. Since of are not commonly included in the molecular arrange- similarity chemical structure is one of the widely ment based on the active groups of acetylcholine. The role accepted criteria for an agonist-antagonist competition on a of such factors is revealed by a study of the observed dif- common receptor (5, 6), the possibility of identifying some of ferences in the cholinergic and psychomimetic activities of the structural features necessary for direct interaction with related pairs of isomers and enantiomers of the molecules the cholinergic receptor is of special interest for the con- investigated. Structural factors which interfere with the conformational changes occurring in the receptor protein sideration of both psychomimetic (e.g., hallucinogenic) and induced by an activator are characterized through dif- anticholinergic activity. We, however, stress that the simi- ferences obtained by the comparative investigation of the larity should be considered in the broader sense of a similar activities of the agonist acetate and the antagonist ben- reactivity pattern characterized by both structural and elec- zilate amino esters of quinuclidine, tropine, and pseudotropine. The same factors are shown in studies of the tronic parameters, as suggested also by Mautner (7). phencyclidine series to contribute to the antagonism The assumption of a common receptor for both agonists to acetylcholine activity that is closely related to the and antagonists has sometimes been disputed (8, 9). However, psychomimetic activity of these drugs in the central attempts to verify the existence of separate receptors related nervous system. Similarly, phencyclidine derivatives in to the different modes of action have not produced unam- which the characteristic acetylcholine-like molecular arrangement is modified by various substitutions are biguous results (10-12). On the other hand, the persistent shown to loose both anticholinergic and psychotropic correlation between the structural elements entailing both behavior. This close correlation is supported by the identi- the psychomimetic and the anticholinergic activity can be fication of molecular regions which will generate the shown to hold also for the hallucinogenic drugs of the phen- proper molecular arrangement in local anesthetics and morphine, compounds which are known to be involved in cycidine [1-(1-phenylcyclohexyl)-piperdineJ series, which do cholinergic mechanisms. not even exhibit an atom-to-atom correspondence with the functional groups of acetylcholine (AcCh). The molecular The biological response characteristic of acetylcholine-like arrangement that represents the standard for the direct activity is commonly considered to be the manifestation of a interaction with the cholinergic receptor is, however, usually certain intrinsic action, triggered by the binding at a specific based on the characteristic functional groups of atoms in receptor (1, 2). Consequently, antagonistic activity has been AcCh-like molecules. The structural requirements for the interpreted as the possible result of shielding the receptor specific interaction of the phencyclidine derivatives with the from interaction with agonists (3). According to this model, cholinergic receptor had, therefore, to be sought in terms of molecular species for which an affinity to the receptor can be a new form of a specific molecular arrangement. This is chosen to be closer to the representation of the dynamic reactivity of Abbreviation: AcCh, acetylcholine. the molecule in the early stages of the recognition by the re- t To whom to address correspondence. ceptor. Such an interaction can be characterized by the pat- 3103 Downloaded by guest on October 3, 2021 3104 Biochemistry: Maayani et al. Proc. Nat. Acad. Sci. USA 70 (1978) sidered in terms of the active molecular groups of AcCh (Fig. 1). This figure represents the spatial and electronic requirements for the direct interaction of certain defined functional sites in the molecule with the cholinergic receptor (15). These functional groups form an "AcCh moiety" which is easily identifiable in the molecules of potent anticholinergic amino esters such as atropine, scopolamine, 3-quinuclidinyl a benzilate and Ditran (a 30:70 mixture of N-ethyl-3-piperi- dino and N-ethyl-2-pyrrolidinomethyl phenylcyclopentyl glycolate). It has been shown, on the other hand, that in the absence of the phenyl rings and the hydroxyl group, these molecules turn into agonists of AcCh (15). Since the AcCh moiety is almost rigid in these molecules, no interference or alteration of the specific structural requirements for interaction with the cholinergic receptor site are to be expected from these changes into amino esters of the acetic acid. The different activity of the resulting species is therefore at- tributed to factors which influence later stages of the drug- receptor interaction, which follow the earlier stage of receptor recognition. The AcCh-like activity of some heterocyclic amino esters on isolated smooth muscle is presented in Table 1. Quantum b OD35 mechanical calculations of the most potent agonist [S(+)-3- FIG. 1. Elements of the interaction pattern of acetylcholine- acetoxyquinucidine HCl] (15), and of the least active ones like molecules with the muscarinic receptor. (a) Distance pattern in this series, tropine and pseudotropine. have shown that for functional groups. (b) Net atomic charges in the [600; 1800] the AcCh-like activity is related to certain energetically conformation of acetylcholine. preferred conformations of the molecules, which bring the AcCh-like functional groups into a spatial relationship that tern of the electrostatic potential which is generated by the corresponds to that of the biologically active species (Fig. 1). molecule in its surroundings. This is considered to represent Moreover, the electron charge distributions in these particular a map of the interaction sites of the molecules in ionic mech- conformations of the molecules, are found to correspond en- anisms (13) that are relevant to the primary stage of the interaction with the receptor (14). Structural requirements for cholinergic activity of amino esters The structural elements leading to the AcCh-like activity of Acetylcholine the psychomimetic drugs of the glycolate series can be con- 3-aQuinu c lidnylT benzilate cN1ii L~~~~~~~~~ ,~~~~~~~~C H .0A ProcaineH2NO-0 AC2H5 D CH2-CH2 C2H5 a b c Morphine FIG. 2. Specific molecular arrangements of AcCh (b) com- pared to those generated by phencyclidine (a) and 3-acetoxy quinuclidine (c). Electrostatic potential maps are calculated analytically (28) for the preferred conformations of AcCh (19) FIG. 3. Molecular regions generating electrostatic potentials and acetoxy quinuclidine (14) and for the x-ray conformation of which form the molecular arrangement of AcCh in quinuclidinyl phencyclidine (36). Dotted regions surrounding the nitrogen atom benzilate and procaine. The two distinct regions of negative correspond to positive potentials (repulsive towards positive potentials which might be generated in morphine [i.e., the charge). Striated regions represent

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