Acetylcholine-Like Molecular Arrangement in Psychomimetic Anticholinergic Drugs

Abstract

A study of the relation between the psychotropic activity and the antagonism to acetylcholine observed for some heterocyclic amino esters and compounds of the phencyclidine series suggests some common molecular structural requirements for their properties.Criteria obtained from quantum mechanical calculations of acetylcholine-like molecules indicate that their molecular reactivity with the cholinergic receptor site follows a certain dynamic interaction pattern. This pattern suggests a certain molecular arrangement essential for the interaction, which is based on the electronic properties of the molecules and therefore remains valid for the evaluation of compounds which lack any apparent similarity to acetylcholine. This type of molecular arrangement is shown to be shared by both activators and inhibitors of the acetylcholine receptor discussed here, thus supporting the hypothesis of their binding to a common receptor. The differences in biological activity are attributed to the effect of molecular structural factors which are not commonly included in the molecular arrangement based on the active groups of acetylcholine. The role of such factors is revealed by a study of the observed differences in the cholinergic and psychomimetic activities of related pairs of isomers and enantiomers of the molecules investigated. Structural factors which interfere with the conformational changes occurring in the receptor protein induced by an activator are characterized through differences obtained by the comparative investigation of the activities of the agonist acetate and the antagonist benzilate amino esters of quinuclidine, tropine, and pseudotropine. The same factors are shown in studies of the phencyclidine series to contribute to the antagonism to acetylcholine activity that is closely related to the psychomimetic activity of these drugs in the central nervous system. Similarly, phencyclidine derivatives in which the characteristic acetylcholine-like molecular arrangement is modified by various substitutions are shown to loose both anticholinergic and psychotropic behavior. This close correlation is supported by the identification of molecular regions which will generate the proper molecular arrangement in local anesthetics and morphine, compounds which are known to be involved in cholinergic mechanisms.The biological response characteristic of acetylcholine-like activity is commonly considered to be the manifestation of a certain intrinsic action, triggered by the binding at a specific receptor (1, 2). Consequently, antagonistic activity has been interpreted as the possible result of shielding the receptor from interaction with agonists (3). According to this model, molecular species for which an affinity to the receptor can be Abbreviation: AcCh, acetylcholine.t To whom to address correspondence.established, but which fail to cause the perturbation entailing the biological response, may be expected to exhibit antagonistic properties. The rationalization of both agonistic and antagonistic activities on the mol...

Structure-activity relationship in a new series of atropine analogs. 1. N,N'-Disubstituted 6,7-diazabicyclo[3.2.2]nonane derivatives

“…flat diameter column; CHCl3-MeOH, 90:10) affording 8 g (43%) of 1: NMR (CDC13) 1.30-1.80 (m, C89-H, 4 ), 1.80-2.10 (m, C24-H, 4 H), 2.44 (s, NCH3, 6 H), 2.86 (m, C16-H, 2 ), 3.46-4.30'(ABC, CHCH2OH, 3 H), 5.34 (quin, J = 6.Ó Hz, C3-H, 1 H), 7.27 (m, Ph, 5 H); IR (neat) 3700-3000, 2950, 1730 (C=0), 1640,1580,1460, 1410, 1300, 1170, 1070,1050,1030, 750, 700 cnT1; MS (m/e) 318 (M+, 100), 303 (M+ -CHa, 55), 288.7 (m*, 318 -303). 6.7-Dimethyl-6,7-diazabicyclo[3.2.2]non-3of-yl Tropate Methiodide (2). A solution of 1 g (3.1 mmol) of 1 and 2 mL (31 mmol) of methyl iodide in 5 mL of acetone was refluxed for 24 h. The suspension obtained was filtered, and the solid was washed with acetone and dried, yielding 1.1 g (77%) of white 2: mp 123-125 °C dec. Anal.…”

“…The present work describes the synthesis of a new series of atropine analogues and their affinities to the muscarinic receptor from guinea pig ileum, in relation to various structural features of the drug-receptor recognition pattern including (1) the C3-site configuration (a//3), (2) the ability to assume various conformations (chair-boat), and (3) N-substitution (tertiary/quaternary).…”