Biochemistry and the Search for Therapeutic Agents

BIOCHEMISTRY AND THE SEARCHFOR THERAPEUTIC AGENTS IRA WEINRYB* A traditional approach to the identification of many types of potential new therapeutic agents has been the examination of novel substances, prepared by the synthetic chemist, in an appropriate animal model system devised by the pharmacologist. By and large, the biochemists' skills have only occasionally been utilized in this search for new medicines. Welch [1] and Smith [2] have pointed out several areas in which the application of cellular and enzymic test systems to the search for drugs has been fruitful. These include the use of (a) inhibitors of nucleic acid and protein biosynthesis to treat neoplasia and viral infection, (b) inhibitors of xanthine oxidase such as allopurinol to attenuate the symptoms of gout, and (c) various inhibitors of dihydrofolate reductase as either cytotoxic drugs or antiparasitic agents. In addition, the recognition that the mood-elevating effects of iproniazid were associated with the inhibition of monoamine oxidase led to the exploitation of this enzyme in the discovery and development of other inhibitors with antidepressive as well as antihypertensive activities [3]. Despite these important successes, the biochemist has not, until very recently, participated consistently in the development of medicines. This was probably because of a lack of understanding of the biochemical events underlying the disease state in most cases. It is the aim of this paper to note that the skills of the biochemist are appropriate to the investigation of a potential drug at several stages of its development and to emphasize that expanding opportunities for primary screening now exist as a result of recent advances in our knowledge ofthe biochemistry ofmany cellular processes. The biochemist may contribute to the development of medicines in several ways. He may devise primary screening tests that utilize cellular or subcellular systems. With such preparations, a large number of compounds may be tested relatively quickly. If the tests are properly selected and designed, an active compound will very likely have an effect in vivo useful in the treatment of a disease state. When a promising compound ?Department of Pharmacology, Squibb Institute for Medical Research, Princeton, New Jersey 08540. 506 I Ira Weinryb · Search for Therapeutic Agents has been identified as having a desirable activity in vivo, the biochemist can explore the cellular and molecular interactions of this agent to furnish information about its possible mode of action. Such investigations can form the basis for the kind of primary screen mentioned above. Studies of the metabolism and pharmacokinetics of drug candidates involve obvious biochemical considerations. Possible metabolites may be discovered from experiments with homogenates of liver or other organs or microsomal fractions derived from such homogenates. The interaction of potential therapeutic agents with serum proteins or other macromolecules may also be examined with biochemical techniques. Of these broad areas the one that appears to possess the most exciting potential is the primary screen at the molecular level. Such potential arises from recent achievements in the translation of the operational pharmacologic concept of"receptors" into biochemically describable entities . The isolation, purification, and manipulation of these fragments of target cells to which hormones, transmitters, and similar molecular messengers bind has resulted in an array of model systems in vitro either directly or indirectly related to a variety of disease syndromes. Many of these models derive from the recognition that several kinds of hormone receptors on the surfaces of many cell types are linked to the plasmamembrane -associated enzyme, adenylate cyclase. Presentation of the appropriate hormone to the cell in suspension or culture, or to a suitable membrane fraction, results in an increase in either intracellular adenosine 3', 5' -monophosphate (cyclic AMP) levels measured or adenylate cyclase activity, respectively [4]. Measurements of adenylate cyclase activity are perhaps more easily interpreted and furnish a basis for the identification of both receptor agonists and antagonists. A few examples of the possible utility of these systems follow: 1.Catecholamine-responsive adenylate cyclases from heart and lung represent functional /3-adrenergic receptor complexes. They can be used to identify selective /3-adrenergic agonists or antagonists [5]. Agonists specific for the lung would be helpful in the treatment of acute bronchial asthma without accompanying cardiac stimulation. Antagonists specific for cardiovascular receptors would be useful in the...