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Characterization of a Novel Series of D4 Dopamine Receptor Ligands Reveals Structure‐Activity Relationships for Selective Partial Agonists
Author(s) -
Day Marilyn M.,
Free R. Benjamin,
Stang Christopher R.T.,
Boateng Comfort A.,
Keck Thomas M.,
Sibley David R.
Publication year - 2018
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.2018.32.1_supplement.827.6
Subject(s) - agonist , partial agonist , functional selectivity , receptor , radioligand , chemistry , dopamine receptor d2 , dopamine , g protein coupled receptor , neuroscience , psychology , pharmacology , biology , biochemistry
D4 dopamine receptors (D4R) are G protein‐coupled receptors that play important roles in cognition, attention, and decision making. D4R ligands have been shown to alter cognition and behavior in animal models of drug addiction and variations in the DRD4 gene have been associated with novelty‐seeking and risk behavior, as well as ADHD. A better understanding of D4R‐mediated signaling is essential to understanding and treating D4R‐associated disorders, including substance abuse disorders. Despite its clinical implications, there are currently few compounds that selectively modulate the D4R receptor. Such compounds are important to study D4R function and identify favorable pharmacology for disease treatment. We created a small next‐generation compound library using computational modelling to design D4R ligands based on the parental scaffold of the prototypical D4R partial agonist A‐412997. This library was analyzed for D2R, D3R, and D4R activity using both agonist and antagonist radioligand competition binding assays and functional signaling readouts (β‐arrestin recruitment and cAMP inhibition). We found that substitutions on the piperidine and pyridine moieties, as well as modifications in linker length, led to several novel lead compounds with improved selectivity and potency, and varying degrees of agonist efficacy. Compounds were identified that displayed high binding affinity (<100 nM) for the D4R coupled with a >1000‐fold selectivity vs. the D3R and D2R. Importantly, these ligands displayed a range of agonist efficacies from highly efficacious partial agonists to full antagonists of the D4R. Interestingly, some compounds with similar binding affinities showed divergent functional efficacies, allowing for the generation of a preliminary structure‐activity relationship underlying functional efficacy. Further optimization may allow for directed tuning of functional efficacy that, when coupled to in vivo behavioral studies, may provide insight into the importance of relative efficacy levels as a means to treat D4R‐related disorders. Support or Funding Information NINDS IRP This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .