Anxiolytic- and antidepressant-like profile of ATC0065 and ATC0175: Nonpeptidic and orally active melanin-concentrating hormone receptor 1 antagonists
Anxiolytic- and antidepressant-like profile of ATC0065 and ATC0175: Nonpeptidic and orally active melanin-concentrating hormone receptor 1 antagonists
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DOI：
10.1124/jpet.104.081711
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发表时间：
2005-05-01
影响因子：
3.5
通讯作者：
Thomsen, W
中科院分区：
文献类型：
--
作者：
Chaki, S;Funakoshi, T;Thomsen, W
黑素浓集激素（MCH）是在下丘脑外侧产生的一种环肽。它涉及许多生理过程，包括摄食行为、能量平衡以及情绪状态的调节。在此，我们报告ATC0065[N - 2 - [顺 - 4 - （{2 - [4 - 溴 - 2 - （三氟甲氧基）苯基]乙基}氨基）环己基] - N4,N4 - 二甲基喹唑啉 - 2,4 - 二胺二盐酸盐]和ATC0175[N - （顺 - 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]这两种新合成的黑素浓集激素受体1（MCHR1）拮抗剂的体外和体内特性。ATC0065和ATC0175对人MCHR1都具有高亲和力，IC50值分别为15.7 ± 1.95和7.23 ± 0.59 nM。通过MCH增加的鸟苷5'-O - （3 - [S - 35]硫代）磷酸（[S - 35]GTPγS）与人MCHR1的结合评估，ATC0065（IC50 = 21.4 ± 1.57 nM）和ATC0175（IC50 = 13.5 ± 0.78 nM）在MCHR1上都显示出强效的拮抗活性。在大鼠强迫游泳试验中，口服给予ATC0065（3 - 30 mg/kg）或ATC0175（1 - 10 mg/kg）显著减少不动时间，表明具有抗抑郁样作用。在大鼠高架十字迷宫试验中，ATC0065和ATC0175都显著逆转游泳应激诱导的焦虑，在小鼠中显著逆转应激诱导的体温过高。ATC0175显著增加陌生大鼠之间的社交互动，并减少豚鼠幼崽分离诱导的发声，表明具有抗焦虑潜力。相比之下，ATC0065和ATC0175不影响大鼠的自发活动或转棒表现。这些发现表明ATC0065和ATC0175是强效且口服有效的MCHR1拮抗剂，在啮齿动物中具有抗焦虑和抗抑郁活性。
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]-N4,N4-dimethylquinazoline-2,4-diamine dihydrochloride] and ATC0175 [N-(cis-4-{[4-(dimethylamino)quinazolin-2-yl]amino}cyclohexyl)3,4- difluorobenzamide hydrochloride], newly synthesized MCH receptor 1 (MCHR1) antagonists. Both ATC0065 and ATC0175 had high affinities for human MCHR1 with IC50 values of 15.7 +/- 1.95 and 7.23 +/- 0.59 nM, respectively. Both ATC0065 (IC50 = 21.4 +/- 1.57 nM) and ATC0175 (IC50 = 13.5 +/- 0.78 nM) showed potent antagonist activities at MCHR1, as assessed by MCH-increased guanosine 5'-O-(3-[S-35]thio)phosphate ([S-35]GTP gamma S) 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.