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Conserved serines of transmembrane 5 in the dopamine D 1 receptor interact with non‐catechol D 1 ligands
Author(s) -
Lee SangMin,
Bhattacharya Supriyo,
Nagarajan Vaidehi,
Mailman Richard
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.883.4
Subject(s) - chemistry , catechol , hydrogen bond , stereochemistry , alanine , transmembrane domain , docking (animal) , homology modeling , dyskinesia , amino acid , biochemistry , parkinson's disease , enzyme , medicine , molecule , disease , nursing , organic chemistry
Full dopamine D 1 agonists have been shown to have excellent efficacy for Parkinson's disease (PD), equal to levodopa, the current gold standard therapy. Unfortunately, no full D 1 agonist has been approved because all current full D 1 agonists have poor oral bioavailability caused by a catechol group. We investigated the binding sites of non‐catechol D 1 ligands using ergoline and tetrahydronaphthalene scaffold backbones to provide a structural basis for new drug design. Homology modeling suggests that several ergoline derivatives show a docking pose close to the conserved serines (S5.42, S5.43, and S5.46) in transmembrane 5 (TM5). Each of these serines was mutated to alanine (S5.42A, S5.43A, and S5.46A) to remove a potential hydrogen bonding site. As predicted, the S5.46A mutation significantly decreased the affinity of ergoline derivatives, and S5.43A mutation showed an equal or less decrease than S5.46 mutation. Conversely, the S5.42A mutation greatly increased the affinity of ergoline derivatives. The affinity of the tetrahydronaphthalene rotigotine was decreased by S5.42A or S5.43A, but not S5.46A indicating possible hydrogen bonding with S5.42 or S5.43. Together, these data suggest that the conserved serines in TM5 influence the interactions of non‐catechol D 1 ligands in site‐ and scaffold‐dependent manners.