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首页> 外文期刊>CNS drug reviews >ATC0175: an orally active melanin-concentrating hormone receptor 1 antagonist for the potential treatment of depression and anxiety.
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ATC0175: an orally active melanin-concentrating hormone receptor 1 antagonist for the potential treatment of depression and anxiety.

机译：ATC0175：一种口服活性的黑色素浓缩激素受体1拮抗剂，可用于治疗抑郁症和焦虑症。

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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-difluoro benzamide 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.
机译：黑色素浓缩激素（MCH）已牵涉到各种生理事件。最近的研究清楚地表明，妇幼保健在压力和情绪调节中起着重要作用。迄今为止，已经鉴定出MCH的两种受体亚型（MCH1R和MCH2R）。已建议MCH1R介导MCH的大多数生理功能。最近，我们合成了MCH1R，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）的口服活性，非肽拮抗剂。该化合物是对MCH1R具有高亲和力且对5-HT1A和5-HT2B受体具有额外亲和力的强效拮抗剂。受体结合和功能测定（MCH诱导的[Ca2 +] i升高）表明ATC0175是MCH1Rs上的非竞争性拮抗剂。 ATC0175在许多焦虑症动物模型中均表现出抗焦虑作用，包括升高的迷宫测试，社交互动测试，压力引起的体温过高和母体分离引起的发声。与其他与压力有关的肽受体拮抗剂（如促肾上腺皮质激素释放因子拮抗剂或加压素V1b受体拮抗剂）一样，ATC0175在含有应激成分的模型中的抗焦虑作用更为明显。 ATC0175在强制游泳测试中也表现出抗抑郁作用。如选择性5-羟色胺再摄取抑制剂所观察到的，ATC0175提高了游泳性能而没有改变攀岩行为。 ATC0175在动物模型中具有足够的ADME谱（合理的口服生物利用度和大脑渗透性）和有效的口服活性。相比之下，ATC0175不会影响自发的自发活动，己烯比考特诱导的睡眠时间，也不会损害旋转脚架的性能。因此，ATC0175可能没有不必要的中枢神经系统副作用，而当前的药物有时会观察到这种副作用。此外，ATC0175在大鼠重复毒性研究中耐受性良好，没有遗传毒性。因此，ATC0175可能有效治疗抑郁症和/或焦虑症患者。

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