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 D1 Dopamine Antagonists

Deborah L. Minor, Steven D. Wyrick, Paul S. Charifson, Val J. Watts, Richard B. Mailman, Richard B. Mailman

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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).

Original languageEnglish (US)
Pages (from-to)4317-4328
Number of pages12
JournalJournal of Medicinal Chemistry
Issue number25
StatePublished - Dec 1 1994

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery


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