Efficacy of Hybrid Tetrahydrobenzo[d]thiazole Based Aryl Piperazines D-264 and D-301 at D₂ and D₃ Receptors

Neurochemical Research
Juan ZhenD E Selley

Abstract

In elucidating the role of pharmacodynamic efficacy at D3 receptors in therapeutic effectiveness of dopamine receptor agonists, the influence of study system must be understood. Here two compounds with D3 over D2 selectivity developed in our earlier work, D-264 and D-301, are compared in dopamine receptor-mediated G-protein activation in striatal regions of wild-type and D2 receptor knockout mice and in CHO cells expressing D2 or D3 receptors. In caudate-putamen of D2 knockout mice, D-301 was ~3-fold more efficacious than D-264 in activating G-proteins as assessed by [(35)S]GTPγS binding; in nucleus accumbens, D-301 stimulated G-protein activation whereas D-264 did not. In contrast, the two ligands exerted similar efficacy in both regions of wild-type mice, suggesting both ligands activate D2 receptors with similar efficacy. In D2 and D3 receptor-expressing CHO cells, D-264 and D-301 appeared to act in the [(35)S]GTPγS assay as full agonists because they produced maximal stimulation equal to dopamine. Competition for [(3)H]spiperone binding was then performed to determine Ki/EC50 ratios as an index of receptor reserve for each ligand. Action of D-301, but not D-264, showed receptor reserve in D3 but not in D2 receptor-expressin...Continue Reading

References

Jun 28, 2016·Pharmacology & Therapeutics·Gian Marco LeggioFilippo Drago

Citations

Jan 1, 1988·Journal of Receptor Research·P J Munson, D Rodbard
Nov 22, 1996·Neuroscience Letters·M F PierceyM Camacho-Ochoa
Apr 1, 1997·Brain Research. Molecular Brain Research·M C DefagotM C Antonelli
Aug 1, 1997·Biochemical Pharmacology·J D Hildebrandt
Jun 29, 1999·Cellular and Molecular Neurobiology·J ObadiahBerta Levavi-Sivan
Jun 18, 2002·Cellular and Molecular Neurobiology·Tal IlaniSara Fuchs
Jun 18, 2002·The Journal of Pharmacology and Experimental Therapeutics·Kevin D BurrisPerry B Molinoff
Apr 30, 2003·Neuron·Raul R GainetdinovRichard T Premont
Nov 4, 2004·Journal of Receptor and Signal Transduction Research·Kim A NeveHeather Trantham-Davidson
Dec 6, 2005·Biochemical and Biophysical Research Communications·Larry S BarakKyeong-Man Kim
Apr 15, 2006·CNS & Neurological Disorders Drug Targets·P SokoloffC Gross
Jun 21, 2006·Synapse·Philip SeemanTomiki Sumiyoshi
Feb 3, 2009·Neuropsychiatric Disease and Treatment·Emma L LaneStephen B Dunnett
Feb 17, 2009·European Journal of Pharmacology·Yoshihiro TadoriTetsuro Kikuchi
Nov 10, 2013·PloS One·Tamara AntonioKenneth Alper
May 17, 2014·Journal of Medicinal Chemistry·Dorothee MöllerPeter Gmeiner
Oct 1, 2014·European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology·Bernard Le Foll, Patricia Di Ciano
Apr 1, 2015·Journal of Medicinal Chemistry·Thomas M KeckAmy Hauck Newman

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