Rorick-Kehn Linda M, Perkins Everett J, Knitowski Karen M, Hart John C, Johnson Bryan G, Schoepp Darryle D, McKinzie David L
Neuroscience Discovery Research Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
J Pharmacol Exp Ther. 2006 Feb;316(2):905-13. doi: 10.1124/jpet.105.091926. Epub 2005 Oct 13.
Numerous studies have indicated that selective agonists of group II metabotropic glutamate (mGlu) receptors, such as LY354740 [(1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate] and LY379268 [(-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate], may be useful in the treatment of many psychiatric disorders, including psychosis, anxiety, and drug withdrawal. Although animal and human studies demonstrate potential therapeutic utility, poor oral bioavailability is a limiting factor in the clinical development of these compounds. Therefore, a novel prodrug approach is being pursued to increase exposure levels of active compound after oral administration. Here, we demonstrate a 10-fold increase in brain, plasma, and cerebrospinal fluid levels of LY354740 after oral prodrug administration. Furthermore, we compare the oral efficacy of the mGlu2/3 receptor agonist LY354740 and its prodrug LY544344 [(1S,2S,5R,6S)-2-[(2'S)-(2'-amino)propionyl]aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride] in rodent models of psychosis and anxiety. Phencyclidine (PCP)-induced hyperlocomotion was dose dependently inhibited in rats receiving oral administration of 30 or 100 mg/kg LY544344, whereas LY354740 did not significantly reverse PCP-mediated behaviors at doses up to 100 mg/kg. Orally administered LY544344 (30 mg/kg) and subcutaneously administered LY354740 (10 mg/kg) attenuated stress-induced hyperthermia in DBA/2 mice, with the prodrug producing anxiolytic effects at lower oral doses than the parent compound. Although oral administration of LY354740 did not significantly affect fear-induced suppression of operant responding in rats, subcutaneously administered LY354740 (10 or 20 mg/kg) and orally administered LY544344 (10 or 30 mg/kg) produced significant anxiolytic effects in this model. The present data confirm that mGlu2/3 receptor agonists produce antipsychotic and anxiolytic effects in animal behavioral models and demonstrate that oral bioavailability of LY354740 was substantially increased using a prodrug strategy.
大量研究表明，II 型代谢型谷氨酸（mGlu）受体的选择性激动剂，如LY354740 [（1S,2S,5R,6S）-2-氨基双环[3.1.0]己烷-2,6-二羧酸一水合物] 和LY379268 [（-）-2-氧杂-4-氨基双环[3.1.0]己烷-4,6-二羧酸]，可能对治疗多种精神疾病有用，包括精神病、焦虑症和药物戒断。尽管动物和人体研究证明了其潜在的治疗效用，但口服生物利用度差是这些化合物临床开发中的一个限制因素。因此，正在寻求一种新的前药方法来提高口服给药后活性化合物的暴露水平。在此，我们证明口服前药给药后，LY354740在脑、血浆和脑脊液中的水平提高了10倍。此外，我们比较了mGlu2/3受体激动剂LY354740及其前药LY544344 [（1S,2S,5R,6S）-2-[（2'S）-（2'-氨基）丙酰基]氨基双环[3.1.0]己烷-2,6-二羧酸盐酸盐] 在精神病和焦虑症啮齿动物模型中的口服疗效。在接受30或100 mg/kg LY544344口服给药的大鼠中，苯环己哌啶（PCP）诱导的运动亢进呈剂量依赖性受到抑制，而LY354740在高达100 mg/kg的剂量下并未显著逆转PCP介导的行为。口服LY5(30 mg/kg) 和皮下注射LY354740 (10 mg/kg) 可减轻DBA/2小鼠的应激诱导体温过高，前药在比母体化合物更低的口服剂量下产生抗焦虑作用。尽管口服LY354740对大鼠恐惧诱导的操作性反应抑制没有显著影响，但皮下注射LY354740 (10或20 mg/kg) 和口服LY544344 (10或30 mg/kg) 在该模型中产生显著抗焦虑作用。目前的数据证实，mGlu2/3受体激动剂在动物行为模型中产生抗精神病和抗焦虑作用，并证明使用前药策略可显著提高LY354740的口服生物利用度。
