CP-122721

The known interactions between the serotonergic and neurokinin systems suggest that serotonin reuptake inhibitor (SSRIs) efficacy may be improved by neurokinin-1 receptor (NK1R) antagonism. In the current studies combination of a subeffective dose of an SSRI (0.3 mg/kg fluoxetine or 0.03 mg/kg citalopram) with a subeffective dose of an NK1R antagonist (0.3 mg/kg aprepitant or 1 mg/kg CP-122,721) produced efficacy in the gerbil forced swim test (FST). Serotonin transporter (SERT) occupancy produced by 1 mg/kg fluoxetine (lowest efficacious dose) was 52 ± 5% and was reduced to 29 ± 4% at 0.3 mg/kg, a dose that was efficacious in combination with 0.3 mg/kg aprepitant or 1 mg/kg CP-122,721; the corresponding NK1R occupancies were 79 ± 4% and 61 ± 4% for aprepitant and CP-122,721, respectively. For citalopram, SERT occupancy at the lowest efficacious dose (0.1 mg/kg) was 50 ± 4% and was reduced to 20 ± 5% at 0.03 mg/kg, a dose that was efficacious when combined with aprepitant (0.3 mg/kg). Aprepitant (10 mg/kg) augmented the serotonin elevation produced by fluoxetine (1 or 10 mg/kg) in the gerbil prefrontal cortex; i.e. NK1R antagonism can modulate serotonin responses. A novel orally-available dual-acting NK1R antagonist/SERT inhibitor BMS-795176 is described; gerbil Ki = 1.4 and 1 nM at NK1R and SERT, respectively. BMS-795176 was efficacious in the gerbil FST; efficacy was observed with 35 ± 3% SERT occupancy and 73 ± 3% NK1R occupancy. The interaction between NK1R antagonism and SERT inhibition to lower the SERT occupancy required for antidepressant-like efficacy suggests that BMS-795176 has the potential to improve efficacy with a reduction in SSRI-associated side effects.

The substance P (SP)/neurokinin (NK)-1 receptor system is involved in many pathological processes. NK-1 receptor antagonists have many promising therapeutic indications. However, the only NK-1 receptor antagonist used in clinical practice is the drug aprepitant and its intravenously administered prodrug, fosaprepitant. In general, NK-1 receptor antagonists are safe and well tolerated.

A search was carried out in Medline using the following terms: adverse events, aprepitant, casopitant, clinical trials, CP-122,721, ezlopitant, fosaprepitant, NK-1 receptor antagonists, randomized, safety, side effects, tolerability and vofopitant.

Most clinical trials have focused on the antiemetic action of aprepitant in cancer patients treated with chemotherapy. However, the efficacy and safety of aprepitant have not been fully tested in other diseases in which the SP/NK-1 receptor system is involved (e.g., cancer, HIV, alcoholism); thus, clinical trials are required. The use of NK-1 receptor antagonists in oncology therapy is quite promising, but to date pharmacological therapy has not exploited the many possible therapies offered by such antagonists.