Assessment of dopamine D₁ receptor affinity and efficacy of three tetracyclic conformationally-restricted analogs of SKF38393. Bioorg Med Chem 2011 Sep 15;19(18):5420-31
Date
08/25/2011Pubmed ID
21862338Pubmed Central ID
PMC3171562DOI
10.1016/j.bmc.2011.07.057Scopus ID
2-s2.0-80052587881 (requires institutional sign-in at Scopus site) 11 CitationsAbstract
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.
Author List
Clark AH, McCorvy JD, Watts VJ, Nichols DEAuthor
John McCorvy PhD Associate Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepineBinding, Competitive
Cells, Cultured
Dose-Response Relationship, Drug
HEK293 Cells
Humans
Models, Molecular
Molecular Conformation
Receptors, Dopamine D1
Stereoisomerism
Structure-Activity Relationship
