Neuropeptide Receptor Modulation 51 Neurokinins

The potential for NK1 antagonists as antidepressants has been the subject of a tremendous amount of research effort over the last decade [35]. At least three compounds (aprepitant, L759274, and CP-122721) showed early evidence of anti-depressant effects in clinical studies. The failure of aprepitant to separate from placebo in Phase III studies was a great disappointment [6]. Nonetheless, NK1 antagonists continue to be of interest for depression therapy since they have been shown to potentiate the activity of SSRIs. The NK1 antagonist vestipitant is currently being evaluated in combination with paroxetine for anxiety and depression. Interestingly, both of these activities have been attained in a single compound, 18, which is both a potent SERT inhibitor (pIC50 = 8.0) and an NK1 antagonist (pIC50 = 8.5) [36]. This compound reportedly increased rat 5-HT levels up to 250% of baseline (measured by microdialysis), and was orally active in the isolation-induced guinea-pig pup vocalization test of anxiety.

NK2 antagonists have primarily been investigated for the treatment of inflammatory conditions such as obstructive airways disease [5]. However, studies in preclinical animal models also suggest a potential role for NK2 antagonists as novel antidepressants. Notably, the NK2 antagonist saredutant displayed antidepressant-like properties in the forced swim test and in maternal separation of guinea pig pups [4]. Clinical trials for the treatment of depression are now in progress.

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