PT - JOURNAL ARTICLE AU - Shigeyuki Chaki AU - Shiho Hirota AU - Takeo Funakoshi AU - Yoshiko Suzuki AU - Sayoko Suetake AU - Taketoshi Okubo AU - Takaaki Ishii AU - Atsuro Nakazato AU - Shigeru Okuyama TI - Anxiolytic-Like and Antidepressant-Like Activities of MCL0129 (1-[(<em>S</em>)-2-(4-Fluorophenyl)-2-(4-isopropylpiperadin-1-yl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine), a Novel and Potent Nonpeptide Antagonist of the Melanocortin-4 Receptor AID - 10.1124/jpet.102.044826 DP - 2003 Feb 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 818--826 VI - 304 IP - 2 4099 - http://jpet.aspetjournals.org/content/304/2/818.short 4100 - http://jpet.aspetjournals.org/content/304/2/818.full SO - J Pharmacol Exp Ther2003 Feb 01; 304 AB - We investigated the effects of a novel melanocortin-4 (MC4) receptor antagonist,1-[(S)-2-(4-fluorophenyl)-2-(4-isopropylpiperadin-1-yl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine (MCL0129) on anxiety and depression in various rodent models. MCL0129 inhibited [125I][Nle4-d-Phe7]-α-melanocyte-stimulating hormone (α-MSH) binding to MC4 receptor with aKi value of 7.9 nM, without showing affinity for MC1 and MC3 receptors. MCL0129 at 1 μM had no apparent affinity for other receptors, transporters, and ion channels related to anxiety and depression except for a moderate affinity for the ς1receptor, serotonin transporter, and α1-adrenoceptor, which means that MCL0129 is selective for the MC4 receptor. MCL0129 attenuated the α-MSH-increased cAMP formation in COS-1 cells expressing the MC4 receptor, whereas MCL0129 did not affect basal cAMP levels, thereby indicating that MCL0129 acts as an antagonist at the MC4 receptor. Swim stress markedly induced anxiogenic-like effects in both the light/dark exploration task in mice and the elevated plus-maze task in rats, and MCL0129 reversed the stress-induced anxiogenic-like effects. Under nonstress conditions, MCL0129 prolonged time spent in the light area in the light/dark exploration task and suppressed marble-burying behavior. MCL0129 shortened immobility time in the forced swim test and reduced the number of escape failures in inescapable shocks in the learned helplessness test, thus indicating an antidepressant potential. In contrast, MCL0129 had negligible effects on spontaneous locomotor activity, Rotarod performance, and hexobarbital-induced anesthesia. These observations indicate that MCL0129 is a potent and selective MC4 antagonist with anxiolytic- and antidepressant-like activities in various rodent models. MC4 receptor antagonists may prove effective for treating subjects with stress-related disorders such as depression and/or anxiety. The American Society for Pharmacology and Experimental Therapeutics