Further definition of the D1 dopamine receptor pharmacophore: Synthesis of trans.6,6a,7,8,9,13b-Hexahydro-5h-benzo[d]naphth[2,1-b]azepines as rigid analogues of β-phenyldopamine

Kitaw Negash, David E. Nichols, Val J. Watts, Richard B. Mailman

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Abstract

In an effort to define further the active geometry of the β- phenyldopamine pharmacophore of certain dopamine D1 agonists, the title compounds have been synthesized as conformationally restricted homologues of the potent benzophenanthridine dopamine D1 agonist dihydrexidine 4a. The dihydroxy secondary amine 5b was evaluated as a potential agonist, whereas the N-methyl compounds 5a and 5c were hypothesized to be antagonists. Surprisingly, none of the three compounds had high affinity for dopamine D1 or D2 receptors. A comparison of the low-energy conformations of these molecules shows that the pendant phenyl ring of 5b is twisted about 28°relative to that of the corresponding ring of 4a. Further, the additional methylene used to expand the C ring of 5b projects toward the α face of the molecule, perhaps suggesting that steric protrusion in this region of the molecule is not tolerated. Finally, the phenethylamine fragment incorporated into these molecules deviates about 30δ from the antiperiplanar conformation postulated to be necessary for agonist activity. On the other hand, the potential antagonist molecules 5a and 5c were compared with the dopamine D1 antagonist SCH 39166 2. The conformations of the former two structures differ quite dramatically from that of 2. The most notable differences lie in the relative orientations of the pendant phenyl rings in the two series, as well as the fact that the ethylamine fragment in 2 approximates a gauche conformation, while the comparable orientation in 5a and 5c more nearly approaches an antiperiplanar conformation. These findings will be used to refine further the model of the dopamine D1 agonist receptor that we have previously developed.

Original languageEnglish (US)
Pages (from-to)2140-2147
Number of pages8
JournalJournal of Medicinal Chemistry
Volume40
Issue number14
DOIs
StatePublished - Jul 4 1997

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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