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首页> 外文期刊>CNS drug reviews >The pharmacology of DMP696 and DMP904, non-peptidergic CRF1 receptor antagonists.
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The pharmacology of DMP696 and DMP904, non-peptidergic CRF1 receptor antagonists.

机译：非肽能CRF1受体拮抗剂DMP696和DMP904的药理作用。

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CRF(1) antagonists DMP696 and DMP904 were designed as drug development candidates for the treatment of anxiety and depression. Both compounds display nanomolar affinity for human CRF(1) receptors, and exhibit >1000-fold selectivity for CRF(1) over CRF(2) receptors and over a broad panel of other proteins. DMP696 and DMP904 block CRF-stimulated adenylyl cyclase activity in cortical homogenates and cell-lines expressing CRF(1) receptors. Both compounds inhibit CRF-stimulated ACTH release from rat pituitary corticotropes. Binding and functional studies indicate that DMP696 and DMP904 behave as noncompetitive full antagonists. DMP696 and DMP904 exhibit anxiolytic-like efficacy in several rat anxiety models. In the defensive withdrawal test, both compounds reduce exit latency with lowest effective doses of 3 and 1 mg/kg, respectively. The anxiolytic-like effect is maintained over 14 days of repeated dosing. In the context of a novel environment used in this test, DMP696 and DMP904 reverse mild stress-induced increases in plasma CORT secretion but at doses 3-4-fold greater than those required for anxiolyticlike efficacy. DMP696 and DMP904 are ineffective in three depression models including the learned helplessness paradigm at doses up to 30 mg/kg. At lowest anxiolytic-like doses, DMP696 and DMP904 occupy >50% CRF(1) receptors in the brain. The in vivo IC(50) values (plasma concentrations required for occupying 50% CRF(1) receptors) estimated based upon free, but not total, plasma concentrations are an excellent correlation with the in vitro IC(50) values. Neither compound produces sedation, ataxia, chlordiazepoxide-like subjective effects or adverse effects on cognition at doses 10-fold higher than anxiolytic-like doses. Neither compound produces physiologically significant changes in cardiovascular, respiratory, gastrointestinal or renal functions at anxiolytic-like doses. DMP696 and DMP904 have favorable pharmacokinetic profiles with good oral bioavailabilities. The overall pharmacological properties suggest that both compounds may be effective anxiolytics with low behavioral side effect liabilities.
机译：CRF（1）拮抗剂DMP696和DMP904被设计为治疗焦虑症和抑郁症的候选药物。两种化合物都显示出对人类CRF（1）受体的纳摩尔亲和力，并且对CRF（1）的选择性超过CRF（2）受体和其他蛋白质，显示出> 1000倍的选择性。 DMP696和DMP904在皮质匀浆和表达CRF（1）受体的细胞系中阻断CRF刺激的腺苷酸环化酶活性。两种化合物均抑制CRF刺激的大鼠垂体促肾上腺皮质激素释放ACTH的释放。结合和功能研究表明DMP696和DMP904表现为非竞争性完全拮抗剂。 DMP696和DMP904在几种大鼠焦虑模型中均表现出抗焦虑作用。在防御性戒断试验中，两种化合物均以3和1 mg / kg的最低有效剂量分别降低了退出潜伏期。在重复给药的14天中保持抗焦虑样作用。在该测试中使用的新型环境中，DMP696和DMP904逆转了轻度应激诱导的血浆CORT分泌增加，但剂量比抗焦虑药所需的剂量高3-4倍。 DMP696和DMP904在三种抑郁模型中均无效，其中包括剂量高达30 mg / kg的习得性无助模式。在最低的抗焦虑剂剂量下，DMP696和DMP904占据大脑中> 50％的CRF（1）受体。基于游离但非总血浆浓度估算的体内IC（50）值（占据50％CRF（1）受体所需的血浆浓度）与体外IC（50）值具有极好的相关性。两种化合物均不会产生比镇痛样剂量高10倍的镇静，共济失调，对氯二氮卓样主观效应或对认知的不利影响。在抗焦虑样剂量下，这两种化合物都不会在心血管，呼吸，胃肠或肾功能方面产生生理上显着的变化。 DMP696和DMP904具有良好的药代动力学特征，并具有良好的口服生物利用度。总体药理特性表明，这两种化合物都可能是有效的抗焦虑药，且行为副作用低。

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