Bioorganic & Medicinal Chemistry 2011-09-15

Assessment of dopamine D₁ receptor affinity and efficacy of three tetracyclic conformationally-restricted analogs of SKF38393.

Alia H Clark, John D McCorvy, Val J Watts, David E Nichols

文献索引：Bioorg. Med. Chem. 19 , 5420-31, (2011)

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摘要

To assess the effect of conformational mobility on receptor activity, the β-phenyl substituent of dopamine D(1) agonist ligands of the phenylbenzazepine class, (±)-6,6a,7,8,9,13b-hexahydro-5H-benzo[d]naphtho[2,1-b]azepine-11,12-diol (8), and its oxygen and sulfur bioisosteres 9 and 10, respectively, were synthesized as conformationally-restricted analogs of SKF38393, a dopamine D(1)-selective partial agonist. Compounds trans-8b, 9, and 10 showed binding affinity comparable to that of SKF38393, but functionally, they displayed only very weak agonist activity. These results suggest that the conformationally-restricted structure of the analogs cannot adopt a binding orientation that is necessary for agonist activity.Copyright © 2011 Elsevier Ltd. All rights reserved.