Drug Repurposing Is a New Opportunity for Developing Drugs against Neuropsychiatric Disorders

Abstract

Better the drugs you know than the drugs you do not know. Drug repurposing is a promising, fast, and cost effective method that can overcome traditional de novo drug discovery and development challenges of targeting neuropsychiatric and other disorders. Drug discovery and development targeting neuropsychiatric disorders are complicated because of the limitations in understanding pathophysiological phenomena. In addition, traditional de novo drug discovery and development are risky, expensive, and time-consuming processes. One alternative approach, drug repurposing, has emerged taking advantage of off-target effects of the existing drugs. In order to identify new opportunities for the existing drugs, it is essential for us to understand the mechanisms of action of drugs, both biologically and pharmacologically. By doing this, drug repurposing would be a more effective method to develop drugs against neuropsychiatric and other disorders. Here, we review the difficulties in drug discovery and development in neuropsychiatric disorders and the extent and perspectives of drug repurposing.

Figure 1

Polypharmacological profiles of antipsychotic drugs. Receptoromic screening identified multiple molecular targets for several antipsychotic drugs. In particulr, clozapine has the high affinity (Ki) to 5-HT serotonin receptors (5-HT2A, 5-HT2C, 5-HT6, and 5-HT7), dopamine receptor (D4), muscarinic receptors, (M1, M2, M3, M4, and M5), adrenergic receptors (α-1 and α-2), and other aminergic receptors. Other antipsychotic drugs also interact with multiple targets. More information can be found at NIMH PDSP database (http://pdspdb.unc.edu/pdspWeb/?site=kidb) (reprinted with permission from Nature Publishing Group).

Figure 2

The molecular targets for cardiopulmonary-associated drugs. Recetoromic screening revealed the molecular targets implicated in fenfluramine. 5-HT2B serotonin receptor was identified as a molecular target for the norfenfluramine (a metabolite of fenfluramine), methylergonovine (a metabolite of the valvular heart disease- and pulmonary hypertension-associated drug methysergide), and dihydroergotamine (potentially associated with valvular heart disease and pulmonary hypertension). The drugs associated with cardio diseases also show high affinity to α-2B adrenergic receptors, whereas fluoxetine and the metabolite norfluoxetine do not. In this heat map, the affinity of the drugs is mapped by color gradient, that is, blue (lower affinity, higher Ki), red (higher affinity, lower Ki), and intermediated color (reprinted with permission from Nature Publishing Group).