Figure 13 Small-molecule NK1 receptor antagonists.

NK receptor antagonists have shown mixed effects in clinical trials.162 The initial target for NK antagonists was pain. Despite robust activity in numerous preclinical models, none of the NK1 antagonists advanced to the clinic showed efficacy.163 Based on the efficacy of MK-869 in the guinea pig vocalization model it was advanced to clinical trials in anxiety and at 300 mg showed initial improvements in depression and anxiety symptoms comparable to the SSRI paroxetine (20 mg) in a 6 week randomized, double-blind, placebo-controlled multicenter study in patients with major depression.164 MK-869 failed to show efficacy in subsequent phase III trials and was discontinued. A backup compound, L-759274, significantly improved HAM-A symptoms and indices of depression. CP-122721 has shown efficacy similar to fluoxetine in depressed patients in a 6 week double-blind, placebo-controlled trial.

Mixed NK1/2 or NK1/2/3 receptor antagonists have also been targeted as anxiolytics,165 the rationale being that blockade of more than one receptor subtype might be a more effective strategy to antagonize the effects of substance P and more efficacious in the treatment of anxiety and depression.

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