Conserved serines of transmembrane 5 in the dopamine D1 receptor interact with non‐catechol D1 ligands

Abstract

Full dopamine D1 agonists have been shown to have excellent efficacy for Parkinson's disease (PD), equal to levodopa, the current gold standard therapy. Unfortunately, no full D1 agonist has been approved because all current full D1 agonists have poor oral bioavailability caused by a catechol group. We investigated the binding sites of non‐catechol D1 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 D1 ligands in site‐ and scaffold‐dependent manners.