MCL0042: a nonpeptidic MC4 receptor antagonist and serotonin reuptake inhibitor with anxiolytic- and antidepressant-like activity.

In the present study, we examined the anxiolytic and antidepressant effects of MCL0042, a novel compound showing activity in both MC4 receptor antagonism and serotonin transporter inhibition. MCL0042 showed relatively high affinity for the MC4 receptor and serotonin reuptake site, as determined by receptor binding assays. MCL0042 attenuated [Nle(4),d-Phe(7)]alpha-MSH-increased cAMP formation in MC4 receptor expressing cells, and it inhibited [(3)H]serotonin uptake by rat brain synaptosomes; thus, MCL0042 is an MC4 receptor antagonist and serotonin transporter inhibitor. Subcutaneous administration of MCL0042 significantly increased the number of licks in a Vogel punished drinking test in rats, and it also significantly attenuated swim stress-induced reduction in time spent in open arms in an elevated plus-maze task in rats, showing the anxiolytic-like potential of MCL0042. Moreover, repeated administration of MCL0042 for 14 days attenuated olfactory bulbectomy-induced locomotor hyperactivity in rats, indicating antidepressant-like potential. These data show that MCL0042 has unique properties of both the MC4 receptor antagonist and serotonin transporter inhibitor, and produces anxiolytic and antidepressant activity in rats. Moreover, blockade of both the MC4 receptor and serotonin reuptake sites might represent a useful approach in the treatment of anxiety and depression.