Froimowitz M, Deng Y, Jacob J N, Li N, Cody V
Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Belmont, MA 02178, USA.
Drug Des Discov. 1995 Aug;13(1):73-81.
The structures and absolute configurations of two N-phenethyl substituted cis- and trans-octahydrobenzo[f]quinolines were determined by X-ray crystallography. The absolute configurations of the enantiomers that have high affinity for dopaminergic receptors were found to be (4aR,10bS) and (4aS,10bS) for the (-)-cis- and (-)-trans-8,9-dihydroxy substituted compounds. This is consistent with previous results for a dopamine agonist pharmacophore. MM2-87 calculations for a cis isomer, which has two alternative chair conformations of the piperidine ring, indicated that the preferred conformer is the same as that observed in the crystal structure. Superposition of the more active cis and trans enantiomers showed that the three dimensional orientations of the phenyl ring and the ammonium group are similar in the two geometrical isomers. The cis isomer, however, has steric bulk out of the plane of the molecule and this appears to result in a loss of agonist efficacy. The addition of the N-phenethyl group to the 7-OH and 7,8-diOH cis compounds, however, appears to be sufficient to restore high affinity for dopaminergic receptors unlike previously synthesized cis compounds. These cis compounds, however, appear to be mixed agonist/antagonists or antagonists on functional assays of dopaminergic activity.
通过X射线晶体学确定了两种N-苯乙基取代的顺式和反式八氢苯并[f]喹啉的结构和绝对构型。发现对多巴胺能受体具有高亲和力的对映体的绝对构型，对于（-）-顺式和（-）-反式8,9-二羟基取代的化合物分别为（4aR，10bS）和（4aS，10bS）。这与多巴胺激动剂药效团的先前结果一致。对具有哌啶环两种交替椅式构象的顺式异构体进行的MM2-87计算表明，优选的构象与晶体结构中观察到的构象相同。活性较高的顺式和反式对映体的叠加显示，在两种几何异构体中，苯环和铵基团的三维取向相似。然而，顺式异构体在分子平面外具有空间位阻，这似乎导致激动剂效力丧失。然而，与先前合成的顺式化合物不同，在7-OH和7,8-二OH顺式化合物中添加N-苯乙基似乎足以恢复对多巴胺能受体的高亲和力。然而，在多巴胺能活性的功能测定中，这些顺式化合物似乎是混合激动剂/拮抗剂或拮抗剂。
