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-tetra hydro-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 an tagonist binding pharmacophore of the D-1 dopamine receptor. Receptor affinity was assessed by competition for [H-3]SCH23390 binding sites i n rat striatal membranes. The 6-bromo-1-phenyltetrahydroisoquinoline a nalog 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 anal og 5 had significantly lower D-1 affinity. Conversely, neither 6-monoh ydroxy- (3) nor 7-monohydroxy-1-phenyltetrahydroisoquinolines (4) had significant affinity for the D-1 receptor. These results demonstrate t hat 6-halo and 7-hydroxy substituents influence D-1 binding affinity o f the 1-phenyltetrahydroisoquinolines in a fashion similar to their ef fects on 1-phenyltetrahydrobenzazepines. azepines. The conformationall y constrained 3-chloro-2-hydroxytetrahydrodibenzoquinolizine 9 had muc h lower affinity relative to the corresponding, and more flexible, 6-c hloro-7-hydroxy-1-phenyltetrahydroisoquinoline 6. Similarly, 2,3-dihyd roxytetrahydrodibenzoquinolizine 10 had much lower D-1 affinity compar ed to dihydrexidine 14, a structurally similar hexahydrobenzo[a]phenan thridine that is a high-affinity full D-1 agonist. Together, these dat a not only confirm the effects of the halo and hydroxy substitutents o n 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 mode ling studies and conformational analyses were conducted using the data from these new analogs in combination with the data from compounds pr eviously synthesized. The resulting geometries were used to refine a w orking model of the D-1 antagonist pharmacophore using conventional qu antitative structure-activity relationships and three-dimensional QSAR (CoMFA).