Minor D L, Wyrick S D, Charifson P S, Watts V J, Nichols D E, Mailman R B
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27599-7360.
J Med Chem. 1994 Dec 9;37(25):4317-28. doi: 10.1021/jm00051a008.
New 1-phenyl-1,2,3,4-tetrahydroisoquinolines and related 5,6,8,9-tetrahydro- 13bH-dibenzo[a,h]-quinolizines were prepared as ring-contracted analogs of the prototypical 1-phenyl-2,3,4,5-tetrahydrobenzazepines (e.g., SCH23390) as a continuation of our studies to characterize the antagonist binding pharmacophore of the D1 dopamine receptor. Receptor affinity was assessed by competition for [3H]SCH23390 binding sites in rat striatal membranes. The 6-bromo-1-phenyltetrahydroisoquinoline analog 2 of SCH23390 1 had D1 binding affinity similar to that for the previously reported 6-chloro analog 6, whereas the 6,7-dihydroxy analog 5 had significantly lower D1 affinity. Conversely, neither 6-monohydroxy- (3) nor 7-monohydroxy-1-phenyltetrahydroisoquinolines (4) had significant affinity for the D1 receptor. These results demonstrate that 6-halo and 7-hydroxy substituents influence D1 binding affinity of the 1-phenyltetrahydroisoquinolines in a fashion similar to their effects on 1-phenyltetrahydrobenzazepines. The conformationally constrained 3-chloro-2-hydroxytetrahydrodibenzoquinolizine 9 had much lower affinity relative to the corresponding, and more flexible, 6-chloro-7-hydroxy-1-phenyltetrahydroisoquinoline 6. Similarly, 2,3-dihydroxytetrahydrodibenzoquinolizine 10 had much lower D1 affinity compared to dihydrexidine 14, a structurally similar hexahydrobenzo[a]phenanthridine that is a high-affinity full D1 agonist. Together, these data not only confirm the effects of the halo and hydroxy substitutents on the parent nucleus but demonstrate the pharmacophoric importance of both the nitrogen position and the orientation of the accessory phenyl ring in modulating D1 receptor affinity and function. Molecular modeling studies and conformational analyses were conducted using the data from these new analogs in combination with the data from compounds previously synthesized. The resulting geometries were used to refine a working model of the D1 antagonist pharmacophore using conventional quantitative structure-activity relationships and three-dimensional QSAR (CoMFA).
作为我们对D1多巴胺受体拮抗剂结合药效团进行表征研究的延续，我们制备了新型的1-苯基-1,2,3,4-四氢异喹啉及相关的5,6,8,9-四氢-13bH-二苯并[a,h]-喹嗪，作为典型的1-苯基-2,3,4,5-四氢苯并氮杂卓（如SCH23390）的环收缩类似物。通过竞争大鼠纹状体膜中[3H]SCH23390结合位点来评估受体亲和力。SCH23390 1的6-溴-1-苯基四氢异喹啉类似物2具有与先前报道的6-氯类似物6相似的D1结合亲和力，而6,7-二羟基类似物5的D1亲和力则显著较低。相反，6-单羟基-（3）和7-单羟基-1-苯基四氢异喹啉（4）对D1受体均无显著亲和力。这些结果表明，6-卤代和7-羟基取代基以与其对1-苯基四氢苯并氮杂卓的影响类似的方式影响1-苯基四氢异喹啉的D1结合亲和力。构象受限的3-氯-2-羟基四氢二苯并喹嗪9相对于相应的、更具柔性的6-氯-7-羟基-1-苯基四氢异喹啉6具有低得多的亲和力。同样，与二氢克辛定14相比，2,3-二羟基四氢二苯并喹嗪10的D1亲和力低得多，二氢克辛定14是一种结构相似的六氢苯并[a]菲啶，是一种高亲和力的完全D1激动剂。总之，这些数据不仅证实了卤代和羟基取代基对母核的影响，而且证明了氮位置和辅助苯环取向在调节D1受体亲和力和功能方面的药效团重要性。利用这些新类似物的数据以及先前合成的化合物的数据进行了分子建模研究和构象分析。所得几何结构用于使用传统的定量构效关系和三维QSAR（CoMFA）来完善D1拮抗剂药效团的工作模型。
