3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine:: A novel brain-penetrant, orally available corticotropin-releasing factor receptor 1 antagonist with efficacy in animal models of alcoholism
3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine:: A novel brain-penetrant, orally available corticotropin-releasing factor receptor 1 antagonist with efficacy in animal models of alcoholism
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DOI：
10.1523/jneurosci.4985-06.2007
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发表时间：
2007-03-07
影响因子：
5.3
通讯作者：
Heilig, Markus
中科院分区：
文献类型：
--
作者：
Gehlert, Donald R.;Cippitelli, Andrea;Heilig, Markus
我们描述了一种新的促肾上腺皮质激素释放因子受体1（CRF 1）拮抗剂，具有临床开发的有利特性，及其在临床前酒精中毒模型中的体内活性。3-（4-氯-2-吗啉-4-基-噻唑-5-基）-8-（1-乙基丙基）-2，6-二甲基咪唑并[1，2- B]哒嗪（MTIP）以亚纳摩尔的亲和力抑制I-125- sauvagine与大鼠垂体膜和克隆的人CRF 1的结合，对CRF 2受体或其他常见药物靶点没有可检测的活性.大鼠口服MTIP后，其ED_（50）约为1.3mg/ kg，口服生物利用度为91.1%。与R121919相比（2，5-二甲基-3-（6-二甲基-4-甲基吡啶-3-基）-7-二丙基氨基-吡唑并[1，5- a]嘧啶）和CP 154526（N-丁基-N-乙基-4，9-二甲基-7-（2，4，6-三甲基苯基）-3，5，7-三氮杂双环[ 4.3.0]壬-2，4，8，10-四烯-2-胺），MTIP具有显著降低的分布容积和清除率。MTIP（1 - 10 mg/ kg）既不影响旷场活动，也不影响高架十字迷宫的基线探索。相比之下，MTIP剂量依赖性地逆转了从3g/ kg酒精剂量戒断的致焦虑作用。类似地，MTIP阻断了具有依赖史的Wistar大鼠和高度酒精偏好的遗传模型中的msP大鼠的过量酒精自我给药，其剂量在非依赖性Wistar大鼠中没有作用。此外，MTIP阻止恢复的压力诱导的酒精寻求在postdependent和遗传选择的msP动物，再次在剂量是无效的非依赖性Wistar大鼠。基于这些发现，MTIP是治疗酒精依赖的有希望的候选者。
We describe a novel corticotropin- releasing factor receptor 1 ( CRF1) antagonist with advantageous properties for clinical development, and its in vivo activity in preclinical alcoholism models. 3-( 4- Chloro- 2- morpholin- 4- yl- thiazol- 5- yl)- 8-( 1- ethylpropyl)- 2,6- dimethylimidazo[ 1,2- b] pyridazine ( MTIP) inhibited I-125- sauvagine binding to rat pituitary membranes and cloned human CRF1 with subnanomolar affinities, with no detectable activity at the CRF2 receptor or other common drug targets. After oral administration to rats, MTIP inhibited 125I- sauvagine binding to rat cerebellar membranes ex vivo with an ED50 of similar to 1.3 mg/ kg and an oral bioavailability of 91.1%. Compared with R121919 ( 2,5- dimethyl- 3-( 6- dimethyl- 4- methylpyridin- 3- yl)- 7- dipropylamino- pyrazolo[ 1,5- a] pyrimidine) and CP154526 ( N-butyl-N-ethyl-4,9- dimethyl- 7-( 2,4,6- trimethylphenyl)- 3,5,7- triazabicyclo[ 4.3.0] nona- 2,4,8,10- tetraen- 2- amine), MTIP had a markedly reduced volume of distribution and clearance. Neither open-field activity nor baseline exploration of an elevated plusmaze was affected by MTIP ( 1 - 10 mg/ kg). In contrast, MTIP dose- dependently reversed anxiogenic effects of withdrawal from a 3 g/ kg alcohol dose. Similarly, MTIP blocked excessive alcohol self- administration in Wistar rats with a history of dependence, and in a genetic model of high alcohol preference, the msP rat, at doses that had no effect in nondependent Wistar rats. Also, MTIP blocked reinstatement of stress-induced alcohol seeking both in postdependent and in genetically selected msP animals, again at doses that were ineffective in nondependent Wistar rats. Based on these findings, MTIP is a promising candidate for treatment of alcohol dependence.