Patrick K S, Caldwell R W, Ferris R M, Breese G R
J Pharmacol Exp Ther. 1987 Apr;241(1):152-8.
The pharmacology of the enantiomers of threo-methylphenidate (MPH) was evaluated in the rat to assess the relative contribution of each isomer to central and peripheral actions of the racemic drug. Fractional recrystallization of binaphthyl phosphate salts of dl-threo-MPH allowed resolution of d-threo-MPH and 92% enrichment of l-threo-MPH. The enantiomeric disposition was monitored using gas chromatographic separation of trifluoroacetylprolyl diastereomeric derivatives. The activity of the d-isomer was greater than the l-isomer in the induction of locomotor activity and the inhibition of tritiated dopamine and l-norepinephrine uptake into striatal and hypothalamic synaptosomes, respectively. Neither isomer produced a significant change in the spontaneous release of tritiated catecholamines from synaptosomes. Destruction of catecholaminergic neurons by 6-hydroxydopamine pretreatment attenuated the locomotor response to d-threo-MPH, indicating the involvement of catecholaminergic neural pathways in the locomotor response. Only the d-enantiomer significantly potentiated the pressor responses to i.v. l-norepinephrine. Receptor site stereoselectively for threo- vs. erythro-MPH is discussed in terms of isomer conformational preferences. These results suggest that synaptic inhibition of catecholamine uptake by d-threo-MPH may be involved fundamentally in behavioral and pressor effects of the racemic drug.
对大鼠中苏式甲基苯丙胺（MPH）对映体的药理学进行了评估，以确定每种异构体对外消旋药物的中枢和外周作用的相对贡献。通过对dl-苏式-MPH的磷酸联萘盐进行分步重结晶，可拆分出d-苏式-MPH并使l-苏式-MPH富集至92%。使用三氟乙酰脯氨酰非对映体衍生物的气相色谱分离法监测对映体的处置情况。在诱导运动活动以及分别抑制纹状体和下丘脑突触体对氚化多巴胺和l-去甲肾上腺素的摄取方面，d-异构体的活性大于l-异构体。两种异构体均未使突触体中氚化儿茶酚胺的自发释放产生显著变化。用6-羟基多巴胺预处理破坏儿茶酚胺能神经元可减弱对d-苏式-MPH的运动反应，表明儿茶酚胺能神经通路参与了运动反应。只有d-对映体显著增强了对静脉注射l-去甲肾上腺素的升压反应。根据异构体的构象偏好讨论了苏式与赤式-MPH的受体位点立体选择性。这些结果表明，d-苏式-MPH对儿茶酚胺摄取的突触抑制作用可能是外消旋药物行为和升压作用的根本原因。
