Synthesis and biological evaluation of 7,8,9,10-tetrahydroimidazo[1,2-c]pyrido[3,4-e]pyrimdin-5(6H)-ones as functionally selective ligands of the benzodiazepine receptor site on the GABA(A) receptor

Benzodiazepines are allosteric modulators of the GABA(A) receptor. The traditionally prescribed benzodiazepines are nonselective and suffer from numerous side effects. Upon the identification of receptor subtypes, we set out to discover selective agents with the anticipation that these agents would...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2002-11, Vol.45 (23), p.5043-5051
Main Authors: Albaugh, Pamela A, Marshall, Lu, Gregory, James, White, Geoff, Hutchison, Alan, Ross, Phil C, Gallagher, Dorothy W, Tallman, John F, Crago, Matt, Cassella, James V
Format: Article
Language:English
Subjects:
Animals
Binding, Competitive
Cerebral Cortex - metabolism
Electrophysiology
GABA Agonists - chemical synthesis
GABA Agonists - chemistry
GABA Agonists - pharmacology
Imidazoles - chemical synthesis
Imidazoles - chemistry
Imidazoles - pharmacology
In Vitro Techniques
Ligands
Male
Motor Activity - drug effects
Oocytes - metabolism
Oocytes - physiology
Pyrimidinones - chemical synthesis
Pyrimidinones - chemistry
Pyrimidinones - pharmacology
Radioligand Assay
Rats
Rats, Sprague-Dawley
Receptors, GABA-A - drug effects
Structure-Activity Relationship
Xenopus laevis
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Summary:Benzodiazepines are allosteric modulators of the GABA(A) receptor. The traditionally prescribed benzodiazepines are nonselective and suffer from numerous side effects. Upon the identification of receptor subtypes, we set out to discover selective agents with the anticipation that these agents would have superior therapeutic potential. Herein, we describe the synthesis and biological evaluation of substituted 7,8,9,10-tetrahydroimidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-ones and disclose that these compounds exhibit functional selectivity at the benzodiazepine receptor of GABA(A) receptor subtypes. The alpha(2)/alpha(3)-selective partial agonist 42 exhibited potent in vivo activity.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0202019