Assessment of dopamine D-1 receptor affinity and efficacy of three tetracyclic conformationally-restricted analogs of SKF38393

作者：Clark Alia H; McCorvy John D; Watts Val J; Nichols David E^*

来源：Bioorganic & Medicinal Chemistry, 2011, 19(18): 5420-5431.

DOI：10.1016/j.bmc.2011.07.057

• Dopamine D-1
• Agonist
• Conformation

To assess the effect of conformational mobility on receptor activity, the beta-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.

• 出版日期2011-9-15