DeMet E M, Vosmer G, Halaris A E
J Neurochem. 1981 Mar;36(3):917-23. doi: 10.1111/j.1471-4159.1981.tb01682.x.
Pridefine (AHR-1118) is a pyrrolidine derivative with clinically established antidepressant efficacy. Previous work from this laboratory indicates that pridefine is a reuptake blocker of catecholamines and serotonin with weak releasing activity. This study characterized the mode of amine uptake inhibition by pridefine as noncompetitive. The uptake experiments were performed utilizing ouabain instead of zero-degree controls to differentiate between the passive and active components of uptake. Furthermore, the passive component was resolved into diffusion and binding of substrate. Correction was made for the effects of ouabain on binding. Kinetic constants determined from Lineweaver-Burk plots were: Km = 3 X 10(-7) M for NE, Km = 9 X 10(-8) M for DA, and Km = 3 X 10(-8) M for 5-HT. Dixon analyses of uptake at various pridefine concentrations indicated noncompetitive inhibition with Ki = 2.5 X 10(-6) M for NE uptake, Ki = 2.0 X 10(-6) M for DA uptake, and Ki = 1 X 10(-5) M for 5-HT uptake. These constants compare well IC50 values for the same transmitters: NE, IC50 = 2.4 X 10(-6) M; DA, IC50 = 2.8 X 10(-6) M; 5-HT, IC50 = 1.0 X 10(-5) M. The in vitro results indicate that pridefine is relatively specific as a catecholamine uptake blocker. It differs from tricyclic antidepressants which are reportedly competitive inhibitors of monoamine uptake. The possible mechanisms by which pridefine acts as a noncompetitive inhibitor are discussed.
普瑞发因（AHR - 1118）是一种具有临床确定抗抑郁疗效的吡咯烷衍生物。本实验室先前的研究表明，普瑞发因是一种具有弱释放活性的儿茶酚胺和血清素再摄取阻滞剂。本研究将普瑞发因对胺摄取的抑制模式表征为非竞争性。摄取实验使用哇巴因而非零度对照来区分摄取的被动和主动成分。此外，被动成分被分解为底物的扩散和结合。对哇巴因对结合的影响进行了校正。从Lineweaver - Burk图确定的动力学常数为：去甲肾上腺素（NE）的Km = 3×10^(-7) M，多巴胺（DA）的Km = 9×10^(-8) M，5 - 羟色胺（5 - HT）的Km = 3×10^(-8) M。在不同普瑞发因浓度下对摄取进行的Dixon分析表明为非竞争性抑制，NE摄取的Ki = 2.5×10^(-6) M，DA摄取的Ki = 2.0×10^(-6) M，5 - HT摄取的Ki = 1×10^(-5) M。这些常数与相同递质的IC50值相当：NE，IC50 = 2.4×10^(-6) M；DA，IC50 = 2.8×10^(-6) M；5 - HT，IC50 = 1.0×10^(-5) M。体外实验结果表明，普瑞发因作为儿茶酚胺摄取阻滞剂具有相对特异性。它不同于据报道为单胺摄取竞争性抑制剂的三环类抗抑郁药。讨论了普瑞发因作为非竞争性抑制剂发挥作用的可能机制。
