A Ligand-Triggered Receptor Conformation Enables the Design of Selective Agonists for the Dopamine 3 Receptor (D3R) Using a Bitopic Strategy.
A Ligand-Triggered Receptor Conformation Enables the Design of Selective Agonists for the Dopamine 3 Receptor (D3R) Using a Bitopic Strategy.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Zaragoza, ES · Author affiliation
Institute for Biocomputation and Physics of Complex Systems (BIFI) and Laboratory of Advanced Microscopy (LMA), University of Zaragoza, Zaragoza 50018, Spain.Location evidence
Los Angeles, US · Author affiliation
Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, California 90089, United States.Location evidence
Galveston, US · Author affiliation
Department of Pharmacology and Toxicology, Center for Addiction Sciences and Therapeutics, University of Texas Medical Branch, Galveston, Texas 77555, United States.Location evidence
Baltimore, US · Author affiliation
Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse - Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224, United States.Location evidence
Houston, US · Author affiliation
Department of Pharmaceutical Science, College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas 77004, United States.Location evidence
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Original abstract
While G protein-coupled receptors (GPCRs) represent the largest drug target family, designing subtype-selective molecules is still a challenge, especially to distinguish among closely related subtypes. One of the most challenging cases is the distinction between dopamine D2R and D3R, pivotal receptors in motor functions and cognition, and targets of Parkinson's disease treatments, schizophrenia, or substance use disorders. Attempts to design D3R-selective molecules with ligands binding toward the first transmembrane helix (the most sequence-diverse and conformationally flexible segment in GPCRs but rarely participating in ligand binding) allowed us to discover a ligand-induced ordering of TM1 unique to D3R, yielding an unexploited selectivity site for drug development. Using rational bitopic drug design and the ligand-triggered conformation of the D3R we designed, synthesized, and characterized the most selective D3R agonists to date, >100,000-fold more selective than available ligands. More specifically, we report D3R partial agonists AB12-82 (6d) and AB13-73A (11), with >575,000- and >750,000-fold subtype selectivity, picomolar potency, and 85% and 49% efficacy, respectively. We also present the most selective full agonists reported to date, AB13-08 (4b) and AB13-46A (9), presenting low and subnanomolar potencies with >2,800- and 6,300-fold selectivity for D3R. Overall, we introduce a first-in-class pharmacological toolbox to dissect the (patho)-physiology of D3R, open new avenues for the design of improved neurotherapeutics, and show that using ligand-induced TM1 reorganizations might represent a promising strategy for the design of subtype-selective molecules in other GPCRs.