Nature and Spatial Relationship of the Prosthetic Chemical Groups Required for Maximal Muscarinic Action

Abstract

It is plausible that para-sympathomimetic stimulant action depends on adjacent prosthetic O2 atoms at a distance of about 5.0 A. and 7.0 A., resp., from 1 or more methyl groups attached to N. Pilo-carpine, arecoline, neostigmine, and physostigmine have the 3 basic prosthetic groups at the same interprosthetic distances postulated for acetylcholine and its aliphatic homologues. The A and B distances are reversed in neostigmine, which may be a further indication that the effector cell does not differentiate between ether and ketone O2 atoms. Quarterni-zation of the amino N of the aliphatic series invariably increases the pharmacologic potency, due to greater availability of methyl on N prosthetic groups. In the aromatic series, quarternization increases the potency only when the interprosthetic distance is optimal. In the inhibitors of acetylcholine stimulation, the 3 prosthetic groups postulated for acetylcholine action are found at the same or nearly the same interprosthetic distance. However, the prosthetic groups are in the center ridge of a large umbrella-like molecule. The simplest concept is that these blocking molecules adhere to the cell surface by the prosthetic groups, and by their adherence and difficult degradation prevent the smaller stimulant molecule from reaching the cell receptors. Nicotinic action of the para-sympathomimetic stimulants can not yet be correlated with the prosthetic groups needed for muscarinic action. Methyl on C interferes with nicotinic action, whereas methyl on N is essential for this action. It is pointed out that the distribution of active prosthetic groups, while perhaps responsible for major drug action, is strongly influenced by associated molecular structure and by the ease of degradation or detoxi-cation of these moieties in the body.