Anxiolytic-Like and Antidepressant-Like Activities of MCL0129 (1-[(S)-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

Abstract

ABSTRACT]-␣-melanocyte-stimulating hormone (␣-MSH) binding to MC4 receptor with a K i value of 7.9 nM, without showing affinity for MC1 and MC3 receptors. MCL0129 at 1 M had no apparent affinity for other receptors, transporters, and ion channels related to anxiety and depression except for a moderate affinity for the 1 receptor, serotonin transporter, and ␣ 1 -adrenoceptor, which means that MCL0129 is selective for the MC4 receptor. MCL0129 attenuated the ␣-MSHincreased 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 antidepressantlike activities in various rodent models. MC4 receptor antagonists may prove effective for treating subjects with stress-related disorders such as depression and/or anxiety.Stress initiates a complex cascade of responses that include endocrine, biochemical, and behavioral events. Many of these responses are initiated by release of corticotropin-releasing factor (CRF) (Owen and Nemeroff, 1991). In addition to activation of the brain CRF system, there are several lines of evidence that melanocortins (MCs), which stem from proopiomelanocortin by enzymatic processing, mediate important behavioral and biochemical responses to stress and, consequently, stress-induced disorders. Among MCs, it was reported that ␣-melanocyte-stimulating hormone (␣-MSH) acts as a neurotransmitter or neuromodulator in the brain (Blasquez et al., 1991), and the relationship between ␣-MSH and adrenocorticotropic hormone (ACTH) and stress has been well documented. ␣-MSH and ACTH induce excessive grooming behavior in rats, a rodent behavioral response to stressful situations (De Barioglio et al., 1991;Adan et al., 1999), and antiserum to ACTH reduces novelty-induced grooming (Dunn et al., 1979). ␣-MSH and ACTH have been shown to inhibit the punish response in the Vogel conflict test in rats (Corda et al., 1990), and microinjection of ␣-MSH into the medial preoptic area and ventromedial nucleus increases anxiety and aggressive behavior (Gonzalez et al., 1996). Moreover, ACTH inhibits social contacts in the social interaction test in rats, an effect indicative of anxiogenic properties (File and Clarke, ...

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