Imidazo[1,2-a]pyrimidines as functionally selective and orally bioavailable GABA(A)alpha2/alpha3 binding site agonists for the treatment of anxiety disorders

A series of high-affinity GABA(A) agonists with good oral bioavailability in rat and dog and functional selectivity for the GABA(A)alpha2 and -alpha3 subtypes is reported. The 7-trifluoromethylimidazopyrimidine 14g and the 7-propan-2-olimidazopyrimidine 14k are anxiolytic in both conditioned and unc...

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Veröffentlicht in:	Journal of medicinal chemistry 2006-01, Vol.49 (1), p.35-38
Hauptverfasser:	Goodacre, Simon C, Street, Leslie J, Hallett, David J, Crawforth, James M, Kelly, Sarah, Owens, Andrew P, Blackaby, Wesley P, Lewis, Richard T, Stanley, Joanna, Smith, Alison J, Ferris, Pushpinder, Sohal, Bindi, Cook, Susan M, Pike, Andrew, Brown, Nicola, Wafford, Keith A, Marshall, George, Castro, José L, Atack, John R
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Animals Anxiety Disorders - drug therapy Binding Sites Biological Availability Cell Line Disease Models, Animal Dogs Dose-Response Relationship, Drug Drug Evaluation, Preclinical GABA-A Receptor Agonists Humans Molecular Structure Patch-Clamp Techniques Pyrimidines - chemical synthesis Pyrimidines - pharmacokinetics Pyrimidines - pharmacology Rats Receptors, GABA-A Structure-Activity Relationship
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Zusammenfassung:	A series of high-affinity GABA(A) agonists with good oral bioavailability in rat and dog and functional selectivity for the GABA(A)alpha2 and -alpha3 subtypes is reported. The 7-trifluoromethylimidazopyrimidine 14g and the 7-propan-2-olimidazopyrimidine 14k are anxiolytic in both conditioned and unconditioned animal models of anxiety with minimal sedation observed at full BZ binding site occupancy.
ISSN:	0022-2623