Antipsychotic agents discovery

Examples abound regarding the role of serendipity in the discovery of new therapeutic approaches, which on closer examination usually turned out to be the result of clinicians paying attention to unexpected clinical effects rather than discounting them. For example, lithium was tried first for hypertension, chlorpro-mazine was initially developed as an anesthetic, and imipramine was originally regarded as an antihistamine and an antipsychotic agent. Without astute clinical observations, these drugs would not have found their niche, nor would clozapine have been revived for the benefit of millions of the most difficult to treat schizophrenic patients. Other examples include the expanded indications of newer... 

Trlcklebank. M.D. et al. (1992) Alternative approaches to the discovery of novel antipsychotic agents. Prog. Drug Res.. 38, 299-336. 

DISCOVERY AND PRECLINICAL EVALUATION OF NOVEL DOPAMINE PARTIAL AGONISTS AS ANTIPSYCHOTIC AGENTS... 

Just as in life, five-membered heterocycles are of utmost importance to drug discovery. The most conspicuous of all is probably atorvastatin (Lipitor), an HMG-CoA inhibitor. Another bioactive pyrrole shown below is an antipsychotic agent. 

The antidepressant properties of these earlier antidepressants were chance discoveries. Imipramine was first developed as a potential antipsychotic, but when Kuhn (2) tested the clinical efficacy of this agent, he found that it only benefited depressed schizophrenic patients. This observation prompted him to test it in patients who were suffering from melancholia. Iproniazid was developed as an antitubercular drug, but the observation that euphoria was a side effect led George Crane ( 3) to conduct clinical trials, which found it useful in purely depressed patients. A year later, Nathan Kline ( 4), following up on this observation, reported positive results when he administered iproniazid to another depressed group. 

The discovery that D and receptors are preferentially expressed in limbic areas has led to efforts to identify selective inhibitors for these receptors that might have antipsychotic efficacy and low risk of extrapyramidal effects. Clozapine has modest selectivity for D receptors over other DA receptor types. D receptors, preferentially localized in cortical and limbic brain regions in relatively low abundance, are upregulated after repeated administration of most typical and atypical antipsychotic drugs. These receptors may contribute to clinical antipsychotic actions, but agents that are selective or mixed DyS antagonists have not proved effective in the treat-... 

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