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Molecular determinants of selectivity and efficacy at the dopamine D3 receptor.
Structural features of the receptor that are critical to selectivity and efficacy can be used to design highly D3R-selective ligands with targeted efficacies and are generalizable to other GPCRs in which the SBP can be targeted by bitopic or allosteric ligands.
A Single Glycine in Extracellular Loop 1 Is the Critical Determinant for Pharmacological Specificity of Dopamine D2 and D3 Receptors
It is demonstrated that the 4-phenylpiperazine moiety in this class of D3R-selective compounds binds to the conserved orthosteric binding site, whereas the extended aryl amide moiety is oriented toward a divergent secondary binding pocket (SBP).
Effects of buspirone and the dopamine D3 receptor compound PG619 on cocaine and methamphetamine self-administration in rhesus monkeys using a food-drug choice paradigm
PG619 did not affect cocaine or MA choice, while buspirone increased low-dose cocaine choice and suggest that food-drug choice paradigms may have greater predictive validity than the use of other schedules of reinforcement.
High Affinity Dopamine D3 Receptor (D3R)-Selective Antagonists Attenuate Heroin Self-Administration in Wild-Type but not D3R Knockout Mice
A series of D3R-selective 4-phenylpiperazines with improved metabolic stability and off-target binding at selected 5-HT receptor subtypes are reported, including compounds 16 and the classic D 3R antagonist SB277011A, which were effective in reducing self-administration of heroin in wild-type but not D2R knockout mice.
Influence of Cocaine History on the Behavioral Effects of Dopamine D3 Receptor-Selective Compounds in Monkeys
An incongruence between in vitro and in vivo assays is suggested and a history of cocaine self-administration can affect in vivo efficacy of D3 receptor-preferring compounds PG 619 and CJB 090, which appear to be dependent on the behavioral assay.
Chiral Resolution and Serendipitous Fluorination Reaction for the Selective Dopamine D3 Receptor Antagonist BAK2-66.
The improved chiral synthesis of the selective dopamine D3 receptor (D3R) antagonist (R)-N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)1H-indole-2-carboxamide (( R )-PG648) is described.
N-(3-fluoro-4-(4-(2-methoxy or 2,3-dichlorophenyl)piperazine-1-yl)butyl)arylcarboxamides as selective dopamine D3 receptor ligands: critical role of the carboxamide linker for D3 receptor selectivity.
A pivotal role is supported for the D3R E2 loop and the carbonyl group in the 4-phenylpiperazine class of compounds and a point of separation between structure-activity relationships at D3 R and D2R is revealed.
Using click chemistry toward novel 1,2,3-triazole-linked dopamine D3 receptor ligands.
Design and synthesis of 1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (citalopram) analogues as novel probes for the serotonin transporter S1 and S2 binding
Structural modifications to the N, 4, 5, and 4' positions of (±)citalopram are reported, and eight analogues were identified with similar potencies to S-1 for decreasing the dissociation of [(3)H]S-1 from the S1 site via allosteric modulation at S2.