ATC 0175 hydrochloride

ATC0175 hydrochloride is a potent, selective and orally active antagonist of melanin-concentrating hormone receptor 1 (MCH1) with IC50 of 13 nM for MCH1. It was also shown to have affinity for 5-HT2B and 5-HT1A receptors with IC50 of 9.66 nM and 16.9 nM respectively.

Melanin-concentrating hormone receptor (MCH1), a member of the G protein-coupled receptor family 1, is an integral plasma membrane protein which binds melanin-concentrating hormone. The protein can inhibit cAMP accumulation and stimulate intracellular calcium flux, and is probably involved in the neuronal regulation of food consumption.

In vitro, assays showed that this compound is a potent antagonist with a high affinity for MCH1R. The receptor binding and the functional assay (MCH-induced increase in [Ca2+]) indicated that ATC0175 is a noncompetitive antagonist at MCH1Rs 1.

In vivo, ATC0175 displayed anxiolytic effects in numerous animal models of anxiety including the social interaction test, elevated plus-maze test, maternal separation-induced vocalization and stress-induced hyperthermia. In addition, ATC0175 treatment also exhibited antidepressant effects in the forced swimming test 2.

References:
1.  Semple G, Tran TA, Kramer B, et al. Pyrimidine-based antagonists of h-MCH-R1 derived from ATC0175: in vitro profiling and in vivo evaluation. Bioorganic & medicinal chemistry letters. 2009;19(21):6166-6171.
2.   Chaki S, Yamaguchi J, Yamada H, et al. ATC0175: an orally active melanin-concentrating hormone receptor 1 antagonist for the potential treatment of depression and anxiety. CNS drug reviews. 2005;11(4):341-352.

Anxiolytic- and antidepressant-like profile of ATC0065 and ATC0175: nonpeptidic and orally active melanin-concentrating hormone receptor 1 antagonists.[Pubmed:15677346]

J Pharmacol Exp Ther. 2005 May;313(2):831-9.

Melanin-concentrating hormone (MCH) is a cyclic peptide produced in the lateral hypothalamus. It has been implicated in a number of physiological processes including feeding behavior, energy balance, and the regulation of emotional states. Here, we report in vitro and in vivo profiles of ATC0065 [N(2)-[cis-4-({2-[4-bromo-2-(trifluoromethoxy)phenyl]ethyl}amino)cyclohexyl]-N(4) , N(4)-dimethylquinazoline-2,4-diamine dihydrochloride] and ATC0175 [N-(cis-4-{[4-(dimethylamino)quinazolin-2-yl]amino}cyclohexyl)-3,4-difluorobenzam ide hydrochloride], newly synthesized MCH receptor 1 (MCHR1) antagonists. Both ATC0065 and ATC0175 had high affinities for human MCHR1 with IC(50) values of 15.7 +/- 1.95 and 7.23 +/- 0.59 nM, respectively. Both ATC0065 (IC(50) = 21.4 +/- 1.57 nM) and ATC0175 (IC(50) = 13.5 +/- 0.78 nM) showed potent antagonist activities at MCHR1, as assessed by MCH-increased guanosine 5'-O-(3-[(35)S]thio)phosphate ([(35)S]GTPgammaS) binding to human MCHR1. Oral administration of ATC0065 (3-30 mg/kg) or ATC0175 (1-10 mg/kg) significantly reduced immobility time in the forced swimming test in rats, indicating antidepressant-like effects. Both ATC0065 and ATC0175 significantly reversed swim stress-induced anxiety in the elevated plus-maze test in rats and stress-induced hyperthermia in mice. ATC0175 significantly increased social interaction between unfamiliar rats and reduced separation-induced vocalizations in guinea pig pups, indicating anxiolytic potential. In contrast, ATC0065 and ATC0175 did not affect spontaneous locomotor activity or rotarod performance in rats. These findings indicate that ATC0065 and ATC0175 are potent and orally active MCHR1 antagonists with anxiolytic and antidepressant activity in rodents.

ATC0175: an orally active melanin-concentrating hormone receptor 1 antagonist for the potential treatment of depression and anxiety.[Pubmed:16614734]

CNS Drug Rev. 2005 Winter;11(4):341-52.

Melanin-concentrating hormone (MCH) has been implicated in a variety of physiological events. Recent studies clearly suggest that MCH plays an important role in the regulation of stress and emotion. To date, two receptor subtypes of MCH (MCH1R and MCH2R) have been identified. MCH1R has been suggested to mediate most of the physiological functions of MCH. Recently, we synthesized an orally active, nonpeptidic antagonist of MCH1R, N-(cis-4-{[4-(dimethylamino)quinazolin-2-yl]amino}cyclohexyl)-3,4-difluorobenzami de hydrochloride (ATC0175). This compound is a potent antagonist with a high affinity for MCH1R and additional affinities for 5-HT1A and 5-HT2B receptors. The receptor binding and the functional assay (MCH-induced increase in [Ca2+]i) indicated that ATC0175 is a noncompetitive antagonist at MCH1Rs. ATC0175 exhibited anxiolytic effects in numerous animal models of anxiety including the elevated plus-maze test, social interaction test, stress-induced hyperthermia and maternal separation-induced vocalization. Like with other stress-related peptide receptor antagonists, such as antagonists of corticotropin-releasing factor or vasopressin V1b receptor antagonists, anxiolytic effects of ATC0175 were more pronounced in models containing a stress component. ATC0175 also exhibited antidepressant effects in the forced swimming test. ATC0175 increased swimming performance without altering climbing behavior, as observed with selective serotonin reuptake inhibitors. ATC0175 has adequate ADME profile (reasonable oral bioavailability and brain penetration) and potent oral activity in animal models. In contrast, ATC0175 did not affect spontaneous locomotor activity, hexobarbital-induced sleeping time and did not impair rotarod performance. Thus, ATC0175 may be devoid of unwanted central nervous system side effects, which are sometimes observed with current medications. In addition, ATC0175 was well tolerated in rat repeated toxicity study, and had no genotoxic liability. Therefore, ATC0175 has the potential to be effective in the treatment of patients with depression and/or anxiety disorders.