Venhuis Bastiaan J, Dijkstra Durk, Wustrow David, Meltzer Len T, Wise Lawrence D, Johnson Stephen J, Wikström Håkan V
Department of Medicinal Chemistry, University Center for Pharmacy, University of Groningen, Antonius Deusinglaan 1, NL-9713 AV Groningen, The Netherlands.
J Med Chem. 2003 Sep 11;46(19):4136-40. doi: 10.1021/jm0307786.
A series of racemic and enantiomerically pure oxime derivatives of the potential anti-Parkinson prodrug 6-(N,N-di-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one (1) were synthesized and pharmacologically evaluated. The oximes induced rotational behavior in the Ungerstedt rat rotation model for Parkinson's disease after oral administration. Especially the unsubstituted oxime ((-)-3) and the acetyl-oxime ((-)-10) induced a pronounced and long lasting effect. In this model, large individual differences were observed in responsiveness to treatment between rats. Though less potent than the parent prodrug, the oxime derivatives of (+/-)-1 and (-)-1 can be orally active, acting as cascade prodrugs.
合成了一系列潜在的抗帕金森前药6-(N,N-二正丙基氨基)-3,4,5,6,7,8-六氢-2H-萘-1-酮(1)的外消旋体和对映体纯的肟衍生物，并进行了药理学评价。在昂格斯泰特帕金森病大鼠旋转模型中，肟类化合物经口服给药后可诱导旋转行为。特别是未取代的肟((-)-3)和乙酰肟((-)-10)诱导了显著且持久的效果。在该模型中，观察到大鼠对治疗的反应存在较大的个体差异。虽然比母体前药效力低，但(+/-)-1和(-)-1的肟衍生物可以口服发挥作用，作为级联前药。
