1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines: a series of potent and selective dopamine D(3) receptor antagonists |
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Authors: | Micheli Fabrizio Bonanomi Giorgio Blaney Frank E Braggio Simone Capelli Anna Maria Checchia Anna Curcuruto Ornella Damiani Federica Fabio Romano Di Donati Daniele Gentile Gabriella Gribble Andy Hamprecht Dieter Tedesco Giovanna Terreni Silvia Tarsi Luca Lightfoot Andrew Stemp Geoff Macdonald Gregor Smith Alex Pecoraro Michela Petrone Marcella Perini Ornella Piner Jacqui Rossi Tino Worby Angela Pilla Maria Valerio Enzo Griffante Cristiana Mugnaini Manolo Wood Martyn Scott Claire Andreoli Michela Lacroix Laurent Schwarz Adam Gozzi Alessandro Bifone Angelo Ashby Charles R Hagan Jim J |
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Affiliation: | Psychiatry Centre of Excellence, Molecular Discovery Research, and Safety Assessment, GlaxoSmithKline Medicine Research Centre, Via Fleming 4, 37135 Verona, Italy. Fabrizio.E.Micheli@gsk.com |
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Abstract: | The discovery of new highly potent and selective dopamine D3 receptor antagonists has recently permitted characterization of the role of the dopamine D3 receptor in a wide range of preclinical animal models. A novel series of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines demonstrating a high level of D3 affinity and selectivity with an excellent pharmacokinetic profile is reported here. In particular, the pyrazolyl derivative 35 showed good oral bioavailability and brain penetration associated with high potency and selectivity in vitro. In vivo characterization of 35 confirmed that this compound blocks the expression of nicotine- and cocaine-conditioned place preference in the rat, prevents nicotine-triggered reinstatement of nicotine-seeking behavior in the rat, reduces oral operant alcohol self-administration in the mouse, increases extracellular levels of acetylcholine in the rat medial prefrontal cortex, and potentiates the amplitude of the relative cerebral blood volume response to d-amphetamine in a regionally specific manner in the rat brain. |
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