5-HT_1A Partial Agonists as Anxiolytics and Antidepressants

Abstract

Agonists of the 5-HT_1A subtype of serotonin receptor have long been known to be efficacious in animal models of anxiety and depression (1). Together with the modest success of prototypes in the clinic, these observations have led to speculation as to their mechanism(s) of action. Particularly daunting has been the task of explaining how 5-HT_1A agonists would be effective in clinical states traditionally viewed as being at opposite ends of a diagnostic continuum. The solution to this puzzle may involve their partial agonist nature which theoretically could provide the optimal degree of intrinsic activity for normalizing 5-HT neurotransmission in both hypo- and hypernormal states. This article will consider the possibility of 5-HT_1A partial agonists as the desired endpoint in anxiolytic and antidepressant drug discovery and the potential therapeutic benefits of designing new molecules with various degrees of agonist potential. Where clinical data are lacking, patient outcomes will be extrapolated from laboratory experiments.