Conformational analysis of D1 dopamine receptor agonists: pharmacophore assessment and receptor mapping

Journal of Medicinal Chemistry
D MottolaRichard B Mailman

Abstract

Compute-aided conformational analysis was used to characterize the agonist pharmacophore for D1 dopamine receptor recognition and activation. Dihydrexidine (DHX), a high-affinity full agonist with limited conformational flexibility, served as a structural template that aided in determining a molecular geometry that would be common for other more flexible, biologically active agonists. The intrinsic activity of the drugs at D1 receptors was assessed by their ability to stimulate adenylate cyclase activity in rat striatal homogenates (the accepted measure of D1 receptor activation). In addition, affinity data on 12 agonists including six purported full agonists (dopamine, dihydrexidine, SKF89626, SKF82958, A70108, and A77636), as well as six less efficacious structural analogs, were obtained from D1 dopamine radioreceptor-binding assays. The active analog approach to pharmacophore building was applied as implemented in the SYBYL software package. Conformational analysis and molecular mechanics calculations were used to determine the lowest energy conformation of the active analogs (i.e., full agonists), as well as the conformations of each compound that displayed a common pharmacophoric geometry. It is hypothesized that DHX and o...Continue Reading

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Citations

Sep 23, 1997·Pharmacology, Biochemistry, and Behavior·A M Deveney, J L Waddington
Jul 31, 2014·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Daniel R RosellLarry J Siever
Dec 31, 2004·Proceedings of the National Academy of Sciences of the United States of America·Anton F FliriRobert A Volkmann
Jan 13, 2015·The Journal of Chemical Physics·Samantha K CallearSilvia Imberti
Sep 4, 2017·Journal of Molecular Modeling·Oscar ParraviciniRicardo D Enriz
Jul 22, 2008·Medicinal Research Reviews·Jing ZhangAo Zhang
Jun 29, 2006·The Journal of Pharmacology and Experimental Therapeutics·Jonathan D UrbanRichard B Mailman
Jun 30, 2005·Molecular Pharmacology·Jessica P Ryman-RasmussenRichard B Mailman
Oct 20, 2004·CNS Drug Reviews·Peter SalmiBjörn Kull
Mar 2, 2021·Medicinal Research Reviews·Yohan MalkiNicolas Masurier
Nov 11, 2005·Journal of Medicinal Chemistry·Scott OloffAlexander Tropsha

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