Receptor binding and the discovery of psychotherapeutic drugs

Abstract The identification of useful new drugs, when not due entirely to serendipity, has often relied on in vivo techniques that are both difficult to interpret and to perform. The receptor binding technique, however, by allowing the direct study of the specific biochemical site of action of most psychotherapeutic drugs has provided a simple, selective, and sensitive method to study drug‐receptor interactions. The biochemical locus of action for a family of drugs can often be identified by comparing their absolute potencies in in vivo systems with their affinities at a number of drug and/or neurotrans mitter receptor binding sites. Once a particular binding site is identified as therapeutically relevant, affinity for this binding site can be used as a screen for novel compounds that may show similar in vivo activity. Detailed structure‐activity relationships can be determined in vitro without the problems of metabolism and differential absorption that complicate in vivo studies. Such studies allow the pinpointing of active sites within the drug molecule for further synthetic manipulations. Receptor binding studies have been essential in the elucidation of the therapeutic mechanisms of neuroleptics, tricyclic antidepressants, opiates, and benzodiazepines. Receptor binding studies are not only useful in the identification and quantification of therapeutically useful drug receptor interactions but have also been invaluable in the study of similar interactions that manifest themselves as drug‐induced side effects. Such studies may eventually allow the development of drugs that are not only more therapeutically potent but are also free of side effects. Radioreceptor assays have also been introduced to measureserum drug levels of neuroleptics, antidepressants, anticholinergics, benzodiazepines and P‐adrenergic antagonists. These methods have the advantage of being quick, sensitive, selective, and inexpensive.