Ekesbo A, Torstenson R, Hartvig P, Carlsson A, Sonesson C, Waters N, Tedroff J, Långström B
Department of Neuroscience, Neurology, University Hospital, Uppsala University, Sweden.
Neuropharmacology. 1999 Mar;38(3):331-8. doi: 10.1016/s0028-3908(98)00200-7.
The substituted (S)-3-phenylpiperidine (-)-OSU6162 belongs to a novel class of functional modulators of dopaminergic systems. In vivo, (-)-OSU6162 has a unique stabilising profile on dopaminergic functions. In vitro this compound exhibits low affinity for the dopamine D2 receptor, but due to its similarity to neuroleptics on brain dopaminergic neurochemistry and different postsynaptic effects it has been characterised as a preferential dopamine autoreceptor antagonist. To further clarify the effects of (-)-OSU6162 on the postjunctional nigrostriatal dopaminergic system, dopamine receptor binding was measured in rhesus monkeys (Macaca mulatta) by positron emission tomography (PET) using the D1 and D2 dopamine receptor radioligands [11C]SCH23390 and [11C]raclopride respectively, before and during continuous intravenous infusions of(-)-OSU6162. Additionally, the test-retest variability of sequential [11C]SCH23390 scans was estimated. Following the administration of (-)-OSU6162, [11C]raclopride binding in striatum was dose-dependently decreased with a 76% reduction occurring after 3.0 mg/kg per h continuous infusion. Whereas (-)-OSU6162 in the lower doses had no effect on [11C]SCH23390 binding, the highest dose, 3.0 mg/kg per h, increased [11C]SCH23390 binding, which may indicate a potentiating effect on D1 dopamine receptor mediated functions. Thus, in contrast to the conditions in vitro, (-)-OSU6162 produces a high displacement of raclopride from D2 receptors in vivo.
取代的（S）-3-苯基哌啶（-）-OSU6162属于一类新型的多巴胺能系统功能调节剂。在体内，（-）-OSU6162对多巴胺能功能具有独特的稳定作用。在体外，该化合物对多巴胺D2受体表现出低亲和力，但由于其在脑多巴胺能神经化学方面与抗精神病药物相似且具有不同的突触后效应，它被表征为一种选择性多巴胺自身受体拮抗剂。为了进一步阐明（-）-OSU6162对黑质纹状体多巴胺能系统突触后连接的影响，在恒河猴（猕猴）中，分别使用D1和D2多巴胺受体放射性配体[11C]SCH23390和[11C]雷氯必利，通过正电子发射断层扫描（PET）在连续静脉输注（-）-OSU6162之前和期间测量多巴胺受体结合情况。此外，还估计了连续[11C]SCH23390扫描的重测变异性。给予（-）-OSU6162后，纹状体中[11C]雷氯必利的结合呈剂量依赖性降低，在每小时3.0mg/kg连续输注后降低了76%。而较低剂量的（-）-OSU6162对[11C]SCH23390的结合没有影响，最高剂量每小时3.0mg/kg则增加了[11C]SCH23390的结合，这可能表明对D1多巴胺受体介导的功能具有增强作用。因此，与体外情况相反，（-）-OSU6162在体内可使雷氯必利从D2受体上大量解离。
