SYNTHESIS AND MOLECULAR MODELING OF 1-PHENYL-1,2,3,4-TETRAHYDROISOQUINOLINES AND RELATED 5,6,8,9-TETRAHYDRO-13BH-DIBENZO[A,H]QUINOLIZINES AS D-1 DOPAMINE ANTAGONISTS

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 D-1 dopamine receptor. Receptor affinity was assessed by competition for [H-3]SCH23390 binding sites in rat striatal membranes. The 6-bromo-1-phenyltetrahydroisoquinoline analog 2 of SCH23390 1 had D-1 binding affinity similar to that for the previously reported 6-chloro analog 6, whereas the 6,7-dihydroxy analog 5 had significantly lower D-1 affinity. Conversely, neither 6-monohydroxy- (3) nor 7-monohydroxy-1-phenyltetrahydroisoquinolines (4) had significant affinity for the D-1 receptor. These results demonstrate that 6-halo and 7-hydroxy substituents influence D-1 binding affinity of the 1-phenyltetrahydroisoquinolines in a fashion similar to their effects on 1-phenyltetrahydrobenzazepines. azepines. 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 D-1 affinity compared to dihydrexidine 14, a structurally similar hexahydrobenzo[a]phenanthridine that is a high-affinity full D-1 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 D-1 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 D-1 antagonist pharmacophore using conventional quantitative structure-activity relationships and three-dimensional QSAR (CoMFA).