Carroll F Ivy, Fox Barbara S, Kuhar Michael J, Howard James L, Pollard Gerald T, Schenk Susan
Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, NC 27709, USA.
Eur J Pharmacol. 2006 Dec 28;553(1-3):149-56. doi: 10.1016/j.ejphar.2006.09.024. Epub 2006 Sep 23.
Several studies suggest that a dopamine transporter uptake inhibitor that has a slower onset and longer duration of action than cocaine in animal behavioral measures and decreases cocaine self-administration would be useful as an indirect dopamine agonist pharmacotherapy to treat cocaine addiction. In the present study, we compared five 3-phenyltropane analogs administered orally in locomotor activity in mice and drug discrimination in rats to gain information concerning relative potency, onset, and duration of action. The compounds were also evaluated for reduction of cocaine self-administration in rats after oral administration. In general, the compounds had a slower onset of action than cocaine and reduced cocaine self-administration. 3beta-(4-Chlorophenyl)-2beta-(3-(4'-methylphenyl)-isoxazol-5-yl)tropane (RTI-336) was the most potent in locomotor activity and drug discrimination; it was less stimulatory than cocaine in the first hour and had the slowest onset and longest duration of action. It also reduced self-administration of two infusion doses of cocaine in the rat.
多项研究表明，一种多巴胺转运体摄取抑制剂在动物行为测试中起效比可卡因慢、作用持续时间长，且能减少可卡因自我给药，作为一种间接多巴胺激动剂药物疗法，有望用于治疗可卡因成瘾。在本研究中，我们比较了五种3-苯基托烷类似物经口服给药后对小鼠运动活性和大鼠药物辨别能力的影响，以获取有关相对效力、起效时间和作用持续时间的信息。这些化合物还在大鼠口服给药后评估了对可卡因自我给药的减少作用。总体而言，这些化合物起效比可卡因慢，且能减少可卡因自我给药。3β-(4-氯苯基)-2β-(3-(4'-甲基苯基)-异恶唑-5-基)托烷(RTI-336)在运动活性和药物辨别方面效力最强；在第一个小时内，它的刺激性比可卡因小，起效最慢且作用持续时间最长。它还减少了大鼠两种注射剂量可卡因的自我给药。
