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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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Schizophrenia is a serious and disabling psychiatric disorder affecting approximately 1% of the world's population. A new generation of atypical antipsychotics has been introduced over the past decade. These atypical antipsychotics have comparable or greater efficacy than traditional antipsychotics in the treatment of the psychotic symptoms of schizophrenia and a much improved neurologic side effect profile. This paper reviews the pharmacological efficacy and safety of a potential atypical antipsychotic, NRA0562.NRA0562 has a high affinity for dopamine D 1 , D 2L , D 4.2 , 5-HT 2A receptors as well as á 1 -adrenoceptors, and has a moderate affinity for H 1 receptors. NRA0562 strongly binds to 5-HT 2A receptors and á 1 -adrenoceptors in the frontal cortex, its binding to striatal D 2 receptors is weaker, similar to that of clozapine.NRA562 displayed potent antipsychotic activities in animal models of schizophrenia, such as methamphetamine (MAP)-induced hyperactivity, apomorphine-induced disruption of pre-pulse inhibition and conditioned avoidance test. NRA0562 is more potent in reversing the inhibitory effects of MAP at A10 than at A9 dopamine neurons. It increased Fos-like immunoreactivity in the nucleus accumbens more effectively than in the dorsolateral striatum, indicating that NRA0562 has the profile of an atypical antipsychotic. In vivo assays for extrapyramidal side effect liability showed that NRA0562 has a low rate of neurological side effects. Thus, NRA0562 may have unique antipsychotic activity with a lower propensity for extrapyramidal side effects.

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