Multitarget Selective Antidepressants Design: Latest Developments, Opportunities and Challenges

For ages, the practice of drug discovery has relied heavily on the one-drug one-target design strategy of medicinal chemistry. However, despite the tremendous advances made in chemical and biological sciences and in the discovery technologies the number of drugs/drug candidates coming out from this one-drug one-target approach is paradoxically dwindling. It is now well recognized that the age old philosophy of medicinal chemistry lacks a fundamental conceptual framework. This is particularly so in disorders such as depression where a multiple of pathways are simultaneously deregulated and which basically result from multiple molecular abnormalities, not just from a defect in a single pathway. The recent times has seen a shift towards one drug-multiple target selective design strategy. This novel paradigm has already produced a diverse set of multiple acting structures for depression. Largely as a consequence of the unacceptable side effects, tolerability and low level of efficacy of the currently used drugs (tricyclic antidepressants, mono amine oxidase and selective serotonin reuptake inhibitors), other new generation agents are increasingly being identified that act at more than one target in depressive disorders. Multitarget selective antidepressant research has produced a number of diverse and novel chemistries with a huge potential for the treatment of this debilitating disorder. This manuscript reviews the latest developments surrounding multitarget selective agents for depression, the benefits of such multi acting agents and the implications for the future design of potent and selective dual, triple or even poly-target active antidepressants.