Chaki Shigeyuki, Yamaguchi Jun-ichi, Yamada Hisaharu, Thomsen William, Tran Thuy-Anh, Semple Graeme, Sekiguchi Yoshinori
Medicinal Pharmacology Laboratory, Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan.
CNS Drug Rev. 2005 Winter;11(4):341-52. doi: 10.1111/j.1527-3458.2005.tb00052.x.
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-difluorobenzamide 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.
黑色素浓缩激素（MCH）与多种生理活动有关。最近的研究清楚地表明，MCH在应激和情绪调节中起重要作用。迄今为止，已鉴定出MCH的两种受体亚型（MCH1R和MCH2R）。有人提出MCH1R介导MCH的大多数生理功能。最近，我们合成了一种口服活性的MCH1R非肽拮抗剂，N-（顺式-4-{[4-（二甲基氨基）喹唑啉-2-基]氨基}环己基）-3,4-二氟苯甲酰胺盐酸盐（ATC0175）。该化合物是一种强效拮抗剂，对MCH1R具有高亲和力，对5-HT1A和5-HT2B受体也有额外亲和力。受体结合和功能测定（MCH诱导的[Ca2+]i增加）表明，ATC0175是MCH1R的非竞争性拮抗剂。ATC0175在多种焦虑动物模型中表现出抗焦虑作用，包括高架十字迷宫试验、社交互动试验、应激诱导的体温过高和母婴分离诱导的发声。与其他与应激相关的肽受体拮抗剂一样，如促肾上腺皮质激素释放因子拮抗剂或血管加压素V1b受体拮抗剂，ATC0175的抗焦虑作用在含有应激成分的模型中更为明显。ATC0175在强迫游泳试验中也表现出抗抑郁作用。与选择性5-羟色胺再摄取抑制剂一样，ATC0175提高了游泳能力，而不改变攀爬行为。ATC0175在动物模型中具有良好的药代动力学性质（合理的口服生物利用度和脑渗透性）和强效口服活性。相比之下，ATC0175不影响自发运动活性、己巴比妥诱导的睡眠时间，也不损害转棒试验表现。因此，ATC0175可能没有目前药物有时会出现的不良中枢神经系统副作用。此外，ATC0175在大鼠重复毒性研究中耐受性良好，且无遗传毒性。因此，ATC0175有可能有效治疗抑郁症和/或焦虑症患者。
