Selective Actions of Substituted Benzamide Drugs on Brain Dopamine Receptors

Abstract

Many classes of neuroleptic drugs exist which exhibit antipsychotic activity in man. However, administration of all currently used drugs also results in the production of a variety of extrapyramidal disturbances including acute dystonia, parkinsonism, akathisia and, most worryingly, tardive dyskinesia (1). Both the beneficial action of antipsychotic drugs and the unwanted motor side effects are believed to be due to the ability of these compounds to interact with brain dopamine receptors. A number of attempts have been made to find neuroleptic compounds which might be antipsychotic but which would not produce extrapyramidal disturbances. Currently it is believed that dopamine receptors in brain are not a single entity (2). There are dopamine receptors located in different areas of the brain and such receptors may also have different anatomical locations within one area of brain. In addition, there are reasons for believing that different populations of dopamine receptors may have distinct biochemical characteristics. A commonly employed division of dopamine receptors is into those linked to the enzyme adenylate cyclase (D-1) and those which act independently of this enzyme (D-2) (3). More recently there have been further sub-divisions of the adenylate cyclase independent receptor population (D-2, D-3, D-4) which distinguish between the agonist and antagonist affinities of these receptor sites (4). However, at the present time these latter divisions cannot be associated with any known physiological function and may represent ligand binding sites rather than receptors. Indeed, currently it is believed that all functional effects produced by neuroleptic drugs in the central nervous system are exerted through their actions on a single adenylate cyclase independent dopamine receptor population (D-2); the function of adenylate cyclase linked receptors in the brain remains unknown (5).