Ring substituents on substituted benzamide ligands indirectly mediate interactions with position 7.39 of transmembrane helix 7 of the D4 dopamine receptor.

The Journal of Pharmacology and Experimental Therapeutics
Spencer S EricksenJohn A Schetz

Abstract

In an effort to delineate how specific molecular interactions of dopamine receptor ligand classes vary between D2-like dopamine receptor subtypes, a conserved threonine in transmembrane (TM) helix 7 (Thr7.39), implicated as a key ligand interaction site with biogenic amine G protein-coupled receptors, was substituted with alanine in D2 and D4 receptors. Interrogation of different ligand chemotypes for sensitivity to this substitution revealed enhanced affinity in the D4, but not the D2 receptor, specifically for substituted benzamides (SBAs) having polar 4- (para) and/or 5- (meta) benzamide ring substituents. D4-T7.39A was fully functional, and the mutation did not alter the sodium-mediated positive and negative allostery observed with SBAs and agonists, respectively. With the exception of the non-SBA ligand (+)-butaclamol, which, in contrast to certain SBAs, had decreased affinity for the D4-T7.39A mutant, the interactions of numerous other ligands were unaffected by this mutation. SBAs were docked into D4 models in the same mode as observed for eticlopride in the D3 crystal structure. In this mode, interactions with TM5 and TM6 residues constrain the SBA ring position that produces distal steric crowding between pyrrolidinyl/...Continue Reading

References

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Citations

May 30, 2013·British Journal of Pharmacology·A J KooistraC de Graaf
Mar 19, 2016·ChemMedChem·Valerio MammoliFabio Del Bello
Apr 3, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Beatriz BueschbellIrina S Moreira
Oct 24, 2018·Journal of Medicinal Chemistry·Márton VassChris de Graaf

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