Targets of Drug Action

Abstract

This article considers early work from the author's laboratory on muscarinic receptor specificity, subtypes, and conformational variability, with the use of nuclear magnetic resonance in pharmacology and the conformational variants of dihydrofolate reductase and general questions of receptors. It also considers some current approaches to drug development and receptor function, particularly as influenced by increasing knowledge of three-dimensional structure of receptors. A CHANGE OF PLANSLike many pharmacologists, my original training was in medicine, and I fully expected to spend my career in clinical work, as a pediatrician. However, immediately after graduation in London, I was seriously ill and one of my frequent visitors was my professor of physiology, Samson Wright. He persuaded me not to go straight into clinical work on recovery but to spend some time in a laboratory. What about joining the new pharmacology department at the Middlesex Hospital Medical School that Cyril Keele was just establishing? he asked. I said that I would, for a year only, but then I got hooked. I began attending the monthly meetings of the Physiological Society (in those days there was no separate pharmacological society), and the major topics presented were concerned with the growing evidence that the role of acetylcholine as a transmitter could be extended from the parasympathetic postganglionic endings to the sympathetic ganglia and the neuromuscular junction. The experimental evidence in favor was developed by WS Feldberg, GL Brown, Bernard Katz, and FC MacIntosh under the genial, but critical approval of our doyen, Sir Henry Dale. These developments were strenuously opposed by JC Eccles, who held to the all electrical theory of synaptic transmission and that all the acetylcholine effects people were looking at were ''epiphenomena.'' This in no way discomforted Feldberg, who wrote of the extension of the theory to the central nervous system with great confidence: ''The present position of the theory of acetylcholine as central transmitter is all but settled.'' Later he added a bit of caution: ''perhaps not the universal central transmitter.'' This all made for a very exciting time, and quite naturally I found myself Annu. Rev. Pharmacol. Toxicol. 2000.40:1-16. Downloaded from www.annualreviews.org Access provided by 52.183.12.225 on