Neurokinin antagonists clinical studies

Rimonabant (382) was also included in a clinical study to assess the safety and efficacy of four novel compounds for the treatment of schizophrenia and psychoaffective disorder [378]. The other compounds included in the trial were a neurokinin NK3 antagonist, a serotonin 2A/2C antagonist and a neurotensin NTSl antagonist. Halopeiidol and placebo groups were used as controls in the study. Sixty-nine patients received (382) (20 mg once per day), which failed to demonstrate efficacy in this trial. The reasons for the lack of efficacy may be due to inadequate dosing or an indication that CBi antagonism is not appropriate in the treatment of this condition. 

The authors interpreted the results as follows FK224 is a dual NK, /NK2 antagonist in a variety of animal assays however, the reported affinities are quite low (substance P-induced contraction of guinea-pig ileum, pA2 6.88 NKA-induced contraction of rat vas deferens, pA2 7.50). These data suggest that the dose of FK.224 used in the clinic may have been too low to effectively block neurokinin receptors in the airways and casts doubt on the interpretation of the earlier bradykinin study. 

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