FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4377029261> ?p ?o ?g. }

• W4377029261 abstract "<b>Abstract ID 15773</b> <b>Poster Board 281</b> Dopamine receptors (DARs) are G-protein coupled receptors (GPCRs) that regulate diverse physiological functions including cognition, mood, movement, and reward-related behaviors, and are involved in the treatment or etiology of many neuropsychiatric disorders including schizophrenia and substance use disorder (SUD). DARs are classified as either D1-like (D1R and D5R) or D2-like (D2R, D3R, and D4R) based on structural homology and pharmacological profiles. Antagonists of D2-like DARs are currently used in the therapies for many neuropsychiatric disorders, but D3R-selective antagonists may be better therapeutics for schizophrenia or SUD as they could attenuate psychotic or drug craving symptoms without the motor side effects frequently produced by D2R-preferring antagonists due to limited distribution of the D3R in the brain. However, discovery of D3R-selective compounds is challenging due to high sequence homology of the D2R and D3R within their orthosteric binding sites, leading to the potential for off-target side effects produced by currently available compounds due to simultaneous antagonism of both subtypes or other closely related receptors. Our lab has endeavored to overcome the selectivity challenges posed by orthosteric antagonists by utilizing a D3R-mediated β-arrestin recruitment assay to screen the NIH Molecular Libraries Program 400,000+ small molecule library for compounds that inhibit the D3R via binding to less conserved allosteric sites. The most potent hit compound, MLS6357, was selective for the D3R versus the D2R and D4R in several functional outputs including β-arrestin recruitment and G-protein activation. Radioligand binding and functional assays using closely related GPCRs revealed that MLS6357 has very limited cross-reactivity with other GPCRs. Additionally, Schild-type functional assays showed that MLS6357 acts as a purely non-competitive negative allosteric modulator (NAM) of the D3R. We synthesized and characterized > 70 analogs of MLS6357 using iterative medicinal chemistry approaches which produced analogs that are 100-fold and 60-fold more potent than the parent compound in D3R-mediated β-arrestin recruitment and G-protein activation assays, respectively, and revealed structure–activity relationships for further optimization of the scaffold. Moreover, some analogs appear to display functional selectivity for inhibition of G-protein activation versus inhibition of β-arrestin recruitment, and vice versa, and some also display inverse agonist activity in G-protein signaling assays. Using in vivo pharmacokinetic experiments in mice via i.p. administration, one of the lead analogs was found to be brain penetrant and achieved sufficient concentrations to occupy the D3R in vivo. To identify the allosteric binding site for the MLS6357 scaffold on the D3R, we utilized various D3R/D2R chimeras, receptor mutants, and molecular modeling techniques to reveal and characterize receptor regions necessary for compound efficacy. Further refinement of the binding pocket for MLS6357 will inform future medicinal chemistry efforts. Ultimately, this novel scaffold may be of benefit as a pharmacological probe or therapeutic lead for D3R-related pathophysiology." @default.
• W4377029261 created "2023-05-19" @default.
• W4377029261 creator A5001658100 @default.
• W4377029261 creator A5002172791 @default.
• W4377029261 creator A5002699549 @default.
• W4377029261 creator A5024664357 @default.
• W4377029261 creator A5028024335 @default.
• W4377029261 creator A5033881901 @default.
• W4377029261 creator A5034202004 @default.
• W4377029261 creator A5036261394 @default.
• W4377029261 creator A5040606659 @default.
• W4377029261 creator A5060032204 @default.
• W4377029261 creator A5067520942 @default.
• W4377029261 creator A5076880355 @default.
• W4377029261 creator A5085380611 @default.
• W4377029261 creator A5087938892 @default.
• W4377029261 date "2023-05-18" @default.
• W4377029261 modified "2023-09-29" @default.
• W4377029261 title "Structure–Activity Relationships of a Brain-Penetrant D3 Dopamine Receptor Negative Allosteric Modulator and Investigation of its Binding Site" @default.
• W4377029261 doi "https://doi.org/10.1124/jpet.122.157730" @default.
• W4377029261 hasPublicationYear "2023" @default.
• W4377029261 type Work @default.
• W4377029261 citedByCount "0" @default.
• W4377029261 crossrefType "proceedings-article" @default.
• W4377029261 hasAuthorship W4377029261A5001658100 @default.
• W4377029261 hasAuthorship W4377029261A5002172791 @default.
• W4377029261 hasAuthorship W4377029261A5002699549 @default.
• W4377029261 hasAuthorship W4377029261A5024664357 @default.
• W4377029261 hasAuthorship W4377029261A5028024335 @default.
• W4377029261 hasAuthorship W4377029261A5033881901 @default.
• W4377029261 hasAuthorship W4377029261A5034202004 @default.
• W4377029261 hasAuthorship W4377029261A5036261394 @default.
• W4377029261 hasAuthorship W4377029261A5040606659 @default.
• W4377029261 hasAuthorship W4377029261A5060032204 @default.
• W4377029261 hasAuthorship W4377029261A5067520942 @default.
• W4377029261 hasAuthorship W4377029261A5076880355 @default.
• W4377029261 hasAuthorship W4377029261A5085380611 @default.
• W4377029261 hasAuthorship W4377029261A5087938892 @default.
• W4377029261 hasBestOaLocation W43770292611 @default.
• W4377029261 hasConcept C135285700 @default.
• W4377029261 hasConcept C15744967 @default.
• W4377029261 hasConcept C166342909 @default.
• W4377029261 hasConcept C169760540 @default.
• W4377029261 hasConcept C170493617 @default.
• W4377029261 hasConcept C185592680 @default.
• W4377029261 hasConcept C199596767 @default.
• W4377029261 hasConcept C2776038425 @default.
• W4377029261 hasConcept C2777503648 @default.
• W4377029261 hasConcept C43587935 @default.
• W4377029261 hasConcept C44208683 @default.
• W4377029261 hasConcept C513476851 @default.
• W4377029261 hasConcept C55493867 @default.
• W4377029261 hasConcept C67847695 @default.
• W4377029261 hasConcept C74187038 @default.
• W4377029261 hasConcept C86803240 @default.
• W4377029261 hasConcept C98274493 @default.
• W4377029261 hasConceptScore W4377029261C135285700 @default.
• W4377029261 hasConceptScore W4377029261C15744967 @default.
• W4377029261 hasConceptScore W4377029261C166342909 @default.
• W4377029261 hasConceptScore W4377029261C169760540 @default.
• W4377029261 hasConceptScore W4377029261C170493617 @default.
• W4377029261 hasConceptScore W4377029261C185592680 @default.
• W4377029261 hasConceptScore W4377029261C199596767 @default.
• W4377029261 hasConceptScore W4377029261C2776038425 @default.
• W4377029261 hasConceptScore W4377029261C2777503648 @default.
• W4377029261 hasConceptScore W4377029261C43587935 @default.
• W4377029261 hasConceptScore W4377029261C44208683 @default.
• W4377029261 hasConceptScore W4377029261C513476851 @default.
• W4377029261 hasConceptScore W4377029261C55493867 @default.
• W4377029261 hasConceptScore W4377029261C67847695 @default.
• W4377029261 hasConceptScore W4377029261C74187038 @default.
• W4377029261 hasConceptScore W4377029261C86803240 @default.
• W4377029261 hasConceptScore W4377029261C98274493 @default.
• W4377029261 hasLocation W43770292611 @default.
• W4377029261 hasOpenAccess W4377029261 @default.
• W4377029261 hasPrimaryLocation W43770292611 @default.
• W4377029261 hasRelatedWork W2003736358 @default.
• W4377029261 hasRelatedWork W2092665404 @default.
• W4377029261 hasRelatedWork W2151186972 @default.
• W4377029261 hasRelatedWork W2559771495 @default.
• W4377029261 hasRelatedWork W2996619659 @default.
• W4377029261 hasRelatedWork W3129083073 @default.
• W4377029261 hasRelatedWork W3175605979 @default.
• W4377029261 hasRelatedWork W4225397178 @default.
• W4377029261 hasRelatedWork W4240308782 @default.
• W4377029261 hasRelatedWork W4377029261 @default.
• W4377029261 isParatext "false" @default.
• W4377029261 isRetracted "false" @default.
• W4377029261 workType "article" @default.