Desai Rajeev I, Kopajtic Theresa A, Koffarnus Mikhail, Newman Amy Hauck, Katz Jonathan L
Psychobiology, Medications Discovery Research Branch, National Institute on Drug Abuse, Intramural Research Program, Department of Health and Human Services, National Institutes of Health, Baltimore, Maryland 21224, USA.
J Neurosci. 2005 Feb 23;25(8):1889-93. doi: 10.1523/JNEUROSCI.4778-04.2005.
There is a large unmet medical need for cocaine addiction treatments. Studies have indicated that the dopamine transporter (DAT) is the primary biological target of cocaine, and most drugs that have DAT affinity have behavioral effects like those of cocaine. However, analogs of benztropine have high DAT affinity and behavioral effects that show varying degrees of similarity to cocaine. We now report the discovery that a benztropine analog, JHW007, with high affinity for the DAT does not have cocaine-like behavioral effects and antagonizes the effects of cocaine. JHW007 occupied the DAT in vivo more slowly than did cocaine and had not reached an apparent plateau up to 270 min after injection. The in vivo binding of cocaine to the DAT suggested rate of DAT occupancy as an important contributor to its behavioral effects, and the slow association with the DAT may provide an explanation for JHW007 being relatively devoid of cocaine-like behavioral effects. The antagonism of cocaine suggests that DAT ligands with reduced cocaine-like activity can function as cocaine antagonists and suggests JHW007 as a lead for discovery of cocaine-abuse pharmacotherapeutics.
对于可卡因成瘾治疗存在大量未满足的医疗需求。研究表明，多巴胺转运体（DAT）是可卡因的主要生物学靶点，大多数具有DAT亲和力的药物都具有类似可卡因的行为效应。然而，苯海索类似物具有高DAT亲和力，但其行为效应与可卡因表现出不同程度的相似性。我们现在报告一项发现，即一种对DAT具有高亲和力的苯海索类似物JHW007不具有类似可卡因的行为效应，并且能拮抗可卡因的效应。JHW007在体内占据DAT的速度比可卡因慢，并且在注射后长达270分钟都未达到明显的平台期。可卡因在体内与DAT的结合表明DAT占据率是其行为效应的一个重要因素，而与DAT的缓慢结合可能解释了JHW007相对缺乏类似可卡因行为效应的原因。可卡因的拮抗作用表明，具有降低的类似可卡因活性的DAT配体可以作为可卡因拮抗剂发挥作用，并表明JHW007可作为发现可卡因滥用药物治疗方法的先导物。
