Scientific Meetings: Some Aspects of Pharmacological Chemistry

Abstract

Abstract A Summary of Three University Lectures given in the Department of Pharmacology, University College, London. January-February, 1949. Only the symptomatic drugs were considered in this series. The first lecture dealt with the significance of total chemical constitution and the theories of modes of drug action1. Examples indicating constitution-action-parallelism were quoted, but it was emphasised that much more data were required to produce a more secure basis for a rational approach. In the next lecture the work on the analgesic substances, particularly on morphine, was discussed2. On the third occasion the chemistry of the parasympathomimetics and parasympatholytics was considered. These drugs are based on acetylcholine, which is not strange to the organism. Acetylcholine has three pharmacological actions, muscarinic, nicotinic and under certain conditions, curare-like. As an ester, it is hydrolysed by the enzymes, cholinesterases of blood cells and plasma and transformed into the weakly active choline. Its re-synthesis may be due to the action of an acetylase, the co-enzyme of which may consist partly of pantothenic acid. Its existence was demonstrated by Feldberg and Mann in brain and by Bülbring and Burn in rabbit heart auricles. There exists also an inactive acetylcholine complex, the formation of which may partly explain the disappearance of the neurohormone. That it also occurs in plants was shown by Feldberg’s discovery of acetylcholine in the stinging nettle. The instability and amphotropic properties of acetylcholine stimulated the pharmacological chemist to synthesise substances with more sustained and clear-cut action. When considering substances which, like acetylcholine, possess parasympathomimetic action, Pfeiffer’s theory of prosthetic3 distances comes to mind, postulating an optimum distance between the N-methyl group and the two oxygen atoms. Thus it can be understood why three natural drugs–muscarine, pilocarpine, and arecoline–show, on the whole, lower activities and have never gained clinical importance. Virtual changes of the acetylcholine molecule itself have produced evidence that the free aminoalkanols are very much weaker and that, for the existence of full muscarinic action, the alcohol group must be esterified and the nitrogen carry at least two methyl groups. When the chain of the alcohol or the acid is elongated, activity falls considerably. There is one exception, and that is when the aminoalkanol chain is branched, as in mecholyl which shows strong muscarinic effect. Acetic acid has been exchanged against other acidic residues, such as carbamic acid in carbachol, thioacetic acid, etc. Transformation of the choline ester into choline ethers produces more stable but less active compounds. An ether-like product was made by Fourneau (2268 F) and found to be very potent indeed. Another ether-like compound is Esmodil which contains a double bond like arecoline and croton betaine methyl ester. The latter, carrying the nitrogen on the acidic side, is very much like acetylcholine though weaker. While choline itself shows very little activity, 3-hydroxymethylpyridine, the alcohol corresponding to nicotinic acid, possesses interesting parasympathomimetic properties. Other aromatic compounds with phenolic groups in place of alcoholic hydroxy groups, show remarkable properties, especially when esterified with carbamic acid.