Bulletin Spring‧Summer 1995

To 'Antagonize' at the Cellular Level A Quest f or P o t e n t i a l P r o s t a c y c l i n Receptor Antagonists Medical science and research have made tremendous progress in the last century. If you have aheadache, or a bodyache, or fever, to cite just a common instance, you no longer have to bear up with it till it subsides naturally, or with the aid of 'home' remedies. Aspirin is a common drug, known to practically every household, and affords quick relief under many circumstances. But, important as the drug may be, it is not free of unwanted side-effects, such as irritation of the stomach lining, and hence not suitable to all people either. So, what is the alternative? The development of a drug which benefits like aspirin, but has no unwanted accompanying effects! Inter-disciplinary Research at CUHK This is, in a simplistic manner of speaking, the ultimate aim of ajoint research project between the departments of pharmacology and chemistry of the University. Prof. Robert L. Jones and Dr. Helen Wise of the former department, and Dr. Henry N.C. Wong of the latter, are working upon acombined research project concerning the synthesis and testing of potential prostacyclin receptor antagonists, and have been awarded HK$1,211,000 for the same in 1992 by the Research Grants Council. To understand the project better, we have to comprehend how 'agonists' and 'antagonists' act upon the body. The Function of 'Agonists' The body is made up of many tiny cells, and one of the main functions of living organisms is the transmission of information between cells within tissues or organs. The receivers of information on the outer surfaces of cells are the receptors—proteins which are activated by specific chemical agents in the body fluid. Those agents which stimulate these receptors are called 'agonists'. (Fig. 1) The body produces its own agonists to achieve its normal physiological functions. For example, histamine induces secretion of acid into the stomach to aid digestion. 'Antagonists' in a Contrary Role An 'antagonist', on the other hand, combines with the receptor, but is not able to induce activation — i.e. it does not switch on the processes leading to a response. As aconsequence, when alarge proportion of the receptor population is occupied by the antagonist, the action of the agonist is blocked, or inhibited. The size of any possible response is accordingly reduced. (Fig. 2) The body does not synthesize antagonists; this is the work of the organic chemist, who acts on the information supplied by the pharmacologist. Agonist molecules activate receptorson the plasma membraneto induce intracellular events which result in aresponseof the cells. An antagonist competes with the agonistfor the receptors and hencereducesthesizeof the response. Gazing into the Crystal Ball How does one attempt to discern the structure of an antagonist and hope to synthesize the compound? Perhaps by simply considering the arrangements of atoms in the natural agonist. The problem is that even the amateur scientist can dream up hundreds of related compounds, which would take thousands of hours to synthesize. What the pharmacologist can do sometimes is identify an existing compound that is intermediate in action between an agonist and an antagonist—this 'partial agonist' cannot maximally Research 19