The Experts below are selected from a list of 75 Experts worldwide ranked by ideXlab platform
Mark J Millan - One of the best experts on this subject based on the ideXlab platform.
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blockade of dopamine d3 receptors in frontal cortex but not in sub cortical structures enhances social recognition in rats similar actions of d1 receptor Agonists but not of d2 antAgonists
European Neuropsychopharmacology, 2009Co-Authors: Florence Loiseau, Mark J MillanAbstract:Though D(3) receptor antAgonists can enhance cognitive function, their sites of action remain unexplored. This issue was addressed employing a model of social recognition in rats, and the actions of D(3) antAgonists were compared to D(1) Agonists that likewise possess pro-cognitive properties. Infusion of the highly selective D(3) antAgonists, S33084 and SB277,011 (0.04-2.5 microg/side), into the frontal cortex (FCX) dose-dependently reversed the deficit in recognition induced by a delay. By contrast, the preferential D(2) antagonist, L741,626 (0.63-5.0) had no effect. The action of S33084 was regionally specific inasmuch as its injection into the nucleus accumbens or striatum was ineffective. A similar increase of recognition was obtained upon injection of the D(1) agonist, SKF81297 (0.04-0.63), into the FCX though it was also active (0.63) in the nucleus accumbens. These data suggest that D(3) receptors modulating social recognition are localized in FCX, and underpin their pertinence as targets for antipsychotic agents.
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dopamine d1 receptor coupling to gs olf and gq in rat striatum and cortex a scintillation proximity assay spa antibody capture characterization of benzazepine Agonists
Neuropharmacology, 2007Co-Authors: Mannoury C La Cour, S Vidal, Valerie Pasteau, D Cussac, Mark J MillanAbstract:Cloned, human dopamine D1 receptors recruit multiple effectors but the G-protein subtype(s) activated by cerebral populations remain poorly defined, a question addressed using a rapid immunocapture technique. In rat striatum, dopamine (DA) and four selective, benzazepine Agonists at D1 receptors concentration-dependently enhanced [35S]GTPγS binding to Gαs/olf. For all drugs, Gαq was also recruited with similar potencies and efficacies. Comparable observations were made in the cortex wherein profiles of Gαs/olf vs Gαq activation were also highly correlated. In contrast to Gαs/olf and Gαq, Gαo and Gαi were activated neither in the striatum nor in the cortex, except for SKF82958. As compared to DA, both SKF81297 and SKF82958 were full Agonists at Gs/olf and Gq in cortex and striatum, whereas SKF38393 behaved as a partial agonist. Likewise, the “atypical” agonist, SKF83959 only partially activated Gαq and also Gs/olf in these two regions. In both striatum and cortex, the selective D1 receptor antagonist, SCH23390, abolished the recruitment of Gαq and Gαs by DA, and the action of DA was partially attenuated by SKF83959. These findings demonstrate that, in native CNS tissue, DA and other D1 receptor Agonists activate Gαs and Gαq with similar potencies and efficacies, suggesting their recruitment via pharmacologically-indistinguishable populations of D1 receptors, and show that SPA technology is well-adapted to study the coupling of native DA receptors.
Tatsuo Furukawa - One of the best experts on this subject based on the ideXlab platform.
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Hyperthermia induced by the dopamine D1 receptor agonist SK&F38393 in combination with the dopamine D2 receptor agonist talipexole in the rat.
Pharmacology Biochemistry and Behavior, 1992Co-Authors: Mariko Nagashima, Hiroshi Kimura, Shin-ichiro Matsumoto, Yamada Katsushi, Tatsuo FurukawaAbstract:The present experiments were performed to investigate the effects of dopamine D1 receptor Agonists given alone or in combination with dopamine D2 receptor Agonists on body temperature in rats. The selective dopamine D1 receptor agonist, 1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol (SK&F38393), produced hyperthermia. However, the dopamine D2 receptor agonist, B-HT 920 (talipexole), and the newly synthesized dopamine D2 receptor agonist, (S)-2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole (SND 919), did not change the temperature. Interestingly, the SK&F38393-induced hyperthermia was enhanced by talipexole and SND 919. The drastic hyperthermia induced by combined administration of dopamine D1 and D2 receptor Agonists was blocked by either the dopamine D1 receptor antagonist, SCH23390, or the dopamine D2 receptor antagonist, spiperone. On the other hand, treatment with prazosin, yohimbine, propranolol, scopolamine, or methysergide failed to affect the marked hyperthermia. The present results suggest that a functional link between dopamine D1 and D2 receptors may be synergistic in the regulation of body temperature and that concurrent stimulation of both dopamine D1 and D2 receptors thereby produces marked hyperthermia in the rat.
Bryan L. Roth - One of the best experts on this subject based on the ideXlab platform.
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Defining Structure–Functional Selectivity Relationships (SFSR) for a Class of Non-Catechol Dopamine D1 Receptor Agonists
2019Co-Authors: Michael L. Martini, Jing Liu, Caroline Ray, Xi-ping Huang, Aarti Urs, Nikhil Urs, John D. Mccorvy, Marc G. Caron, Bryan L. RothAbstract:G protein-coupled receptors (GPCRs) are capable of downstream signaling through distinct noncanonical pathways such as β-arrestins in addition to the canonical G protein-dependent pathways. GPCR ligands that differentially activate the downstream signaling pathways are termed functionally selective or biased ligands. A class of novel non-catechol G protein-biased Agonists of the dopamine D1 receptor (D1R) was recently disclosed. We conducted the first comprehensive structure–functional selectivity relationship study measuring GS and β-arrestin2 recruitment activities focused on four regions of this scaffold, resulting in over 50 analogs with diverse functional selectivity profiles. Some compounds became potent full Agonists of β-arrestin2 recruitment, while others displayed enhanced GS bias compared to the starting compound. Pharmacokinetic testing of an analog with an altered functional selectivity profile demonstrated excellent blood–brain barrier penetration. This study provides novel tools for studying ligand bias at D1R and paves the way for developing the next generation of biased D1R ligands
Roth B.l. - One of the best experts on this subject based on the ideXlab platform.
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Defining Structure-Functional Selectivity Relationships (SFSR) for a Class of Non-Catechol Dopamine D1 Receptor Agonists
American Chemical Society, 2019Co-Authors: Martini M.l., Liu J., Ray C., Yu X., Huang X.-p., Urs A., Urs N., Mccorvy J.d., Caron M.g., Roth B.l.Abstract:G protein-coupled receptors (GPCRs) are capable of downstream signaling through distinct noncanonical pathways such as β-arrestins in addition to the canonical G protein-dependent pathways. GPCR ligands that differentially activate the downstream signaling pathways are termed functionally selective or biased ligands. A class of novel non-catechol G protein-biased Agonists of the dopamine D1 receptor (D1R) was recently disclosed. We conducted the first comprehensive structure-functional selectivity relationship study measuring GS and β-arrestin2 recruitment activities focused on four regions of this scaffold, resulting in over 50 analogs with diverse functional selectivity profiles. Some compounds became potent full Agonists of β-arrestin2 recruitment, while others displayed enhanced GS bias compared to the starting compound. Pharmacokinetic testing of an analog with an altered functional selectivity profile demonstrated excellent blood-brain barrier penetration. This study provides novel tools for studying ligand bias at D1R and paves the way for developing the next generation of biased D1R ligands. Copyright © 2019 American Chemical Society
Herbert Y. Meltzer - One of the best experts on this subject based on the ideXlab platform.
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D1 receptor Agonists reverse the subchronic phencyclidine (PCP)-induced novel object recognition (NOR) deficit in female rats
Behavioural brain research, 2012Co-Authors: Masakuni Horiguchi, Kayleen E. Hannaway, Adesewa E. Adelekun, Mei Huang, Karu Jayathilake, Herbert Y. MeltzerAbstract:Development of dopamine (DA) D(1) receptor Agonists is a priority to improve cognitive impairment in schizophrenia (CIS). This study examined the dose-response relationship of the selective D(1) agonist, SKF38393 (0.5-40 mg/kg), to reverse the deficit in novel object recognition (NOR), an analog of declarative memory in man, produced by subchronic phencyclidine (PCP), an N-methyl-D-aspartate (NMDA) receptor non-competitive antagonist, and the ability of the D(1) antAgonists, SCH23390 (0.05 mg/kg) and SKF83566 (0.15 mg/kg), to impair NOR in normal Long-Evans female rats. We also examined the ability of tandospirone, a serotonin (5-HT)(1A) receptor partial agonist, and LY341495, a mGluR2/3 receptor antagonist, to potentiate or block the effects of SKF38393 on NOR, respectively. SKF38393 reversed the persistent NOR deficit produced by subchronic PCP; the dose-response curve for SKF38393 was an inverted U-shape, with the peak effect at 6 mg/kg. SKF83566 and SCH23390 impaired NOR in normal rats. Co-administration of sub-effective doses of SKF38393 (0.25 mg/kg) and tandospirone (0.2 mg/kg) improved the PCP-induced NOR deficit, while LY341495 (1 mg/kg) blocked the ameliorating effect of SKF38393 (6 mg/kg), respectively. These data provide the first evidence that the reversal of the PCP-induced NOR deficit by D(1) agonism has an inverted U-shaped dose-response curve and that 5-HT(1A) and mGluR2/3 receptor signalling facilitates the efficacy of D(1) agonism to improve these deficits. These data suggest that although D(1) Agonists may be useful to improve CIS, these agents, particularly higher doses, may also worsen cognitive function in some patients, because of an inverted U-shaped dose response curve.
