To `Antagonize' at the Cellular Level

Medical science and research have made tremendous progress in the last century. If you have a headache, 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!

This is, in a simplistic manner of speaking, the ultimate aim of a joint 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 a combined 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 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.

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 a consequence, when a large 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.

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 activate the receptor system on its own, but can, to some extent, inhibit the action of the natural agonist. It hence represents an important clue to the structure of a pure antagonist.

The natural agonist `prostacyclin' is best known for its ability to prevent the clumping of blood platelets and to increase blood flow through tissues. However, it is also a powerful stimulant of sensory nerve endings. Released with prostaglandin E₂ at the site of inflammation, it can cause redness, heat, swelling and pain.

CUHK researchers are now trying to develop antagonists for the prostaglandin receptors in the body. In the case of the prostacyclin receptor, a partial agonist which is structurally distinct from the native prostacyclin molecule has been identified. Synthetic pathways to relatives of this structure have been devised and are under investigation. Unequivocal structural identification of each final compound relies heavily upon sophisticated chemical analysis such as nuclear magnetic resonance spectometry and mass spectometry.

Any potential prostacyclin receptor antagonist then undergoes careful biological testing, which involves the use of isolated tissue preparations (like a segment of intestine) obtained from men and animals. Experience has proved that it is possible to keep these preparations `alive' by immersing them in a warmed salt solution, which is a source of oxygen and nutrients. The preparation responds to the prostacyclin agonist as it would in the body, and thus permits the activity of the potential antagonist to be tested.

The programme of synthesis is being continually modified in the light of the results of the biological testing. It is hoped that any potential receptor antagonists developed in this project will have distinct advantages over the currently available aspirin-like drugs. These widely used agents exert their anti-inflammatory and analgesic effects by blocking the biosynthesis of prostaglandins in the affected tissue, for example the knee joint. However they also block prostaglandin biosynthesis throughout the body, and this may not be beneficial. The greater selectivity of the receptor antagonist may be a distinct advantage.