Knoerzer T A, Nichols D E, Brewster W K, Watts V J, Mottola D, Mailman R B
Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907.
J Med Chem. 1994 Jul 22;37(15):2453-60. doi: 10.1021/jm00041a025.
Racemic trans-10,11-dihydroxy-5,6,6a,7,8,12b- hexahydrobenzo[a]phenanthridine (2, dihydrexidine) was shown previously to be the first bioavailable full efficacy agonist at the D1 dopamine receptor. In addition to its full D1 agonist properties, 2 also is a good ligand for D2-like dopamine receptors. The profound anti-Parkinsonian actions of this compound make determination of its enantioselectivity at both D1 and D2 receptors of particular importance. To accomplish this, the enantiomers were resolved by preparation of diastereomeric (R)-O-methylmandelic acid amides of racemic trans-10,11-dimethoxy-5,6,6a,7,8,12b- hexahydrobenzo[a]phenanthridine 4 that were then separated by centrifugal chromatography. An X-ray analysis of the (-)-N-(R)-O-methylmandel diastereoamide revealed the absolute configuration to be 6aS,12bR. Removal of the chiral auxiliary and O,O-deprotection afforded enantiomeric amines that were then tested for biological activity. In striatal membranes, the (6aR,12bS)-(+)-enantiomer 2 had about twice the affinity of the racemate and 25-fold greater affinity than the (-)-enantiomer at the D1 receptor labeled by [3H]SCH23390 (K0.5s of 5.6, 11.6, and 149 nM, respectively). Similarly, the (+)-enantiomer 2 had about twice the affinity of the racemate for human D1 receptors expressed in transfected Ltk- cells. Functionally, the (+)-enantiomer of 2 was a full agonist, with an EC50 of 51 nM in activating striatal dopamine-sensitive adenylate cyclase versus 2.15 microM for the (-)-enantiomer. With respect to D2-like receptors, (+)-2 had a K0.5 of 87.7 nM in competing with [3H]spiperone at D2 binding sites in rat striatal membranes versus about 1 microM for the (-)-enantiomer. Together, these data demonstrate that both the D1 and D2 activities of dihydrexidine reside principally in the (6aR,12bS)-(+)-enantiomer. The results are discussed in the context of structure-activity relationships and conceptual models of the D1 receptor.
外消旋反式-10,11-二羟基-5,6,6a,7,8,12b-六氢苯并[a]菲啶（2，二氢麦角隐亭）先前已被证明是首个可生物利用的、对D1多巴胺受体具有完全药效的激动剂。除了其完全的D1激动剂特性外，2还是D2样多巴胺受体的良好配体。该化合物显著的抗帕金森病作用使得确定其在D1和D2受体上的对映选择性尤为重要。为实现这一点，通过制备外消旋反式-10,11-二甲氧基-5,6,6a,7,8,12b-六氢苯并[a]菲啶4的非对映体（R）-O-甲基扁桃酸酰胺来拆分对映体，然后通过离心色谱法进行分离。对（-）-N-（R）-O-甲基扁桃酸非对映体酰胺的X射线分析表明其绝对构型为6aS,12bR。去除手性辅助基团并进行O,O-脱保护得到对映体胺，然后对其进行生物活性测试。在纹状体膜中，（6aR,12bS）-（+）-对映体2在由[3H]SCH23390标记的D1受体上的亲和力约为外消旋体的两倍，比对映体（-）-2高25倍（K0.5分别为5.6、11.6和149 nM）。同样，（+）-对映体2对转染Ltk-细胞中表达的人D1受体的亲和力约为外消旋体的两倍。在功能上，2的（+）-对映体是完全激动剂，激活纹状体多巴胺敏感腺苷酸环化酶的EC50为51 nM，而（-）-对映体为2.15 μM。关于D2样受体，在大鼠纹状体膜的D2结合位点上，（+）-2与[3H]螺哌隆竞争时的K0.5为87.7 nM，而（-）-对映体约为1 μM。总之，这些数据表明二氢麦角隐亭的D1和D2活性主要存在于（6aR,12bS）-（+）-对映体中。将在D1受体的构效关系和概念模型的背景下讨论这些结果。
