Markowitz John S, DeVane C Lindsay, Pestreich Linda K, Patrick Kennerly S, Muniz Rafael
Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
J Child Adolesc Psychopharmacol. 2006 Dec;16(6):687-98. doi: 10.1089/cap.2006.16.687.
dl-Methylphenidate (MPH) has been widely used to treat attention-deficit/hyperactivity disorder (ADHD) for the last half century. It had been exclusively available in the racemic form, i.e., a 50:50 mixture of d- and l-isomers. However, a single enantiomer formulation, d-MPH (dexmethylphenidate), became available for general clinical use in 2002. For this reason, the intrinsic pharmacological differences in the effects of d- and l-MPH have recently come under intense investigation. The primary therapeutic effects of MPH are generally recognized to reside in the d-isomer. The present investigation provides quantitative values for a broad range of receptor-level interactions of the individual MPH isomers to better characterize the distinction between dl-MPH versus d-MPH versus l-MPH as it relates to binding affinity at sites associated with relevant central nervous system (CNS) pharmacology, as well as peripheral physiology. Overall, there were few differences in binding affinities between d-MPH and the racemate whereas there were more apparent differences between d-MPH and l-MPH. d-MPH exhibited prominent affinity at the norepinephrine transporter (NET) site, even exceeding such affinity at the dopamine transporter (DAT). These results further demonstrate that affinity for catecholaminergic sites largely resides in the d-MPH isomer. Although binding affinity was not demonstrable at the serotonin (5-HT) transporter site (SERT), novel findings of the study included affinity for the 5-HT1A and 5-HT2B receptor sites for both d- and l-MPH, with d-MPH exerting by far the most predominant effects at these sites. Thus, the emerging data of favorable therapeutic effects of ADHD treatment with d-MPH (and dl-MPH) may be underpinned by affinity and potential pharmacologic effects at NET and DAT sites, as well as sites relevant to serotonergic neurotransmission that may modulate mood, cognition, and motor behavior. However, the present exploratory studies reflect receptor binding affinities only. The specific pharmacological activities (i.e., agonism vs. antagonism) of these compounds await further exploration.
在过去的半个世纪里，消旋甲基苯丙胺（MPH）被广泛用于治疗注意力缺陷多动障碍（ADHD）。它一直仅以外消旋体形式存在，即d - 异构体和l - 异构体的50:50混合物。然而，单一对映体制剂d - MPH（右旋甲基苯丙胺）于2002年开始用于一般临床治疗。因此，d - MPH和l - MPH作用的内在药理学差异最近受到了深入研究。MPH的主要治疗作用通常被认为存在于d - 异构体中。本研究提供了一系列MPH异构体在受体水平相互作用的定量值，以更好地描述消旋MPH与d - MPH与l - MPH之间的区别，这涉及到与相关中枢神经系统（CNS）药理学以及外周生理学相关位点的结合亲和力。总体而言，d - MPH与外消旋体之间的结合亲和力差异不大，而d - MPH与l - MPH之间的差异更为明显。d - MPH在去甲肾上腺素转运体（NET）位点表现出显著的亲和力，甚至超过其在多巴胺转运体（DAT）的亲和力。这些结果进一步证明，对儿茶酚胺能位点的亲和力主要存在于d - MPH异构体中。虽然在5 - 羟色胺（5 - HT）转运体位点（SERT）未显示出结合亲和力，但该研究的新发现包括d - MPH和l - MPH对5 - HT1A和5 - HT2B受体位点均有亲和力，其中d - MPH在这些位点发挥的作用最为显著。因此，d - MPH（和消旋MPH）治疗ADHD的良好治疗效果的新出现数据可能是由其在NET和DAT位点以及与5 - 羟色胺能神经传递相关位点的亲和力和潜在药理作用所支撑，这些位点可能调节情绪、认知和运动行为。然而，目前的探索性研究仅反映了受体结合亲和力。这些化合物的具体药理活性（即激动作用与拮抗作用）有待进一步探索。
