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首页> 美国卫生研究院文献>CNS Drug Reviews >Pharmacological Profile of the Selective FAAH Inhibitor KDS‐4103 (URB597)
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Pharmacological Profile of the Selective FAAH Inhibitor KDS‐4103 (URB597)

机译：选择性FAAH抑制剂KDS‐4103（URB597）的药理特性

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In the present article, we review the pharmacological properties of KDS‐4103 (URB597), a highly potent and selective inhibitor of the enzyme fatty‐acid amide hydrolase (FAAH), which catalyzes the intracellular hydrolysis of the endocannabinoid anandamide. In vitro, KDS‐4103 inhibits FAAH activity with median inhibitory concentrations (IC50) of 5 nM in rat brain membranes and 3 nM in human liver microsomes. In vivo, KDS‐4103 inhibits rat brain FAAH activity after intraperitoneal (i.p.) administration with a median inhibitory dose (ID50) of 0.15 mg/kg. The compound does not significantly interact with other cannabinoid‐related targets, including cannabinoid receptors and anandamide transport, or with a broad panel of receptors, ion channels, transporters and enzymes. By i.p. administration to rats and mice KDS‐4103 elicits significant, anxiolytic‐like, antidepressant‐like and analgesic effects, which are prevented by treatment with CB1 receptor antagonists. By contrast, at doses that significantly inhibit FAAH activity and substantially raise brain anandamide levels, KDS‐4103 does not evoke classical cannabinoid‐like effects (e.g., catalepsy, hypothermia, hyperphagia), does not cause place preference, and does not produce generalization to the discriminative effects of the active ingredient of cannabis, Δ9‐tetrahydrocannabinol (Δ9‐THC). These findings suggest that KDS‐4103 acts by enhancing the tonic actions of anandamide on a subset of CB1 receptors, which may normally be engaged in controlling emotions and pain. KDS‐4103 is orally available in rats and cynomolgus monkeys. Sub‐chronic repeated dose studies (1500 mg/kg, per os) in these two species have not demonstrated systemic toxicity. Likewise, no toxicity was noted in bacterial cytotoxicity tests in vitro and in the Ames test. Furthermore, no deficits were observed in rats on the rotarod test after acute i.p. treatment with KDS‐4103 at doses up to 5 mg/kg or in a functional observation battery after oral doses up to 1500 mg/kg. The results suggest that KDS‐4103 will offer a novel approach with a favorable therapeutic window for the treatment of anxiety, depression and pain.
机译：在本文中，我们综述了KDS‐4103（URB597）的药理特性，KDS‐4103是一种强效且选择性的酶脂肪酸酰胺水解酶（FAAH）抑制剂，可催化内源性大麻素anandamide的细胞内水解。在体外，KDS-4103抑制FAAH活性，大鼠脑膜中抑制浓度（IC50）为5 nM，人肝微粒体为3 nM。在体内，腹膜内（i.p.）给药后，KDS-4103抑制大鼠脑FAAH活性，中位抑制剂量（ID50）为0.15μmg/ kg。该化合物不会与其他大麻素相关靶标（包括大麻素受体和Anandamide转运蛋白）或广泛的受体，离子通道，转运蛋白和酶发生显着相互作用。由i.p.向大鼠和小鼠施用KDS-4103会产生显着的抗焦虑样，抗抑郁样和镇痛作用，但可通过使用CB1受体拮抗剂治疗来预防。相比之下，在显着抑制FAAH活性并显着提高脑中的Anandamide水平的剂量下，KDS-4103不会引起经典的大麻素样作用（例如，僵直，低体温，吞咽过多），不会引起位置偏爱，也不会产生泛化作用。大麻活性成分Δ9-四氢大麻酚（Δ9-THC）的鉴别作用。这些发现表明，KDS-4103的作用是通过增强邻氨基苯甲酰胺对一部分CB1受体的强直作用而起作用的，而CB1受体通常可参与控制情绪和疼痛。大鼠和食蟹猴可口服获得KDS-4103。在这两个物种中，亚慢性重复剂量研究（1500μmg/ kg，每os）尚未显示出全身毒性。同样，在体外细菌细胞毒性试验和艾姆斯试验中均未发现毒性。此外，在急性腹膜内注射后，在轮转试验中未观察到大鼠赤字。口服剂量最高1500μmg/ kg后，以5μmg/ kg的剂量用KDS-4103或在功能观察组中进行治疗。结果表明，KDS-4103将提供一种新颖的方法，为焦虑，抑郁和疼痛的治疗提供有利的治疗窗口。

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