The 5HT1A area has been studied in Section; however, interest in this area still persists based on the ability of azapirone partial agonists (e.g., gepirone (52), isapirone (53), and zalospirone (54)) to modify 5HT function by an action on the 5HT autoreceptor. Other 5HT1A agonist compounds in this class include GR127935 (55) and WAY163426, which are reported to raise serotonin levels more rapidly than an SSRI, and exhibit activity in chronic models of depression that are consistent with a more rapid onset. VPI-013 (56) and PRX-00023 (57) have mixed 5HT1A receptor antagonist and sigma agonist properties and are currently in Phase II studies. 5HT1B/D ligands mediate their effects at autoreceptors involved in the local inhibitory control of 5HT release and may play a role in the pathogenesis of MDD and the antidepressant effects of the SSRIs in patients. A number of compounds in this class include GR125743 (58), SB-224289 (59), and L-694247 (60). AZD8129 (61), a 5HT1B antagonist, and CP-448187 (62), a 5HT1B/1D receptor antagonist, are in Phase II studies for depression.

Although SSRIs lower the sensitivity of postsynaptic 5HT receptors, their primary action is to facilitate 5HT neurotransmission by increasing synaptic 5HT levels.54 A potential for 5HT2A receptors is based on the antidepressant efficacy of nefazadone (63), a combined SSRI and 5HT2A receptor antagonist that has been 'black boxed' by the FDA and taken off the market in Europe due to risk-benefit analysis, including consideration of the risk of hepatic failure associated with nefazadone treatment. Other 5HT receptor targets under examination include 5HT2C selective agonists (e.g., WAY163909 (64), Ro-60-0175 (65), Ro-60-0332, Org-12962 (66)). Paradoxically, 5HT2C receptor inverse agonists (e.g., SB-243213 (67) and WAY163909) are also believed to be in development for the treatment of depression.55 The fact that both compounds show a similar pharmacology in several animal models of depression reflects the ability of the 5HT2C receptor agonists and antagonists to desensitize the 5HT2C receptor as observed following chronic SSRI treatment.

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