Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Pharmacol Exp Ther
2009 Feb 01;3282:448-57. doi: 10.1124/jpet.108.146464.
Show Gene links
Show Anatomy links
Novel, potent, and selective GABAC antagonists inhibit myopia development and facilitate learning and memory.
Chebib M
,
Hinton T
,
Schmid KL
,
Brinkworth D
,
Qian H
,
Matos S
,
Kim HL
,
Abdel-Halim H
,
Kumar RJ
,
Johnston GA
,
Hanrahan JR
.
???displayArticle.abstract???
This study reports pharmacological and physiological effects of cis- and trans-(3-aminocyclopentanyl)butylphosphinic acid (cis- and trans-3-ACPBPA). These compounds are conformationally restricted analogs of the orally active GABA(B/C) receptor antagonist (3-aminopropyl)-n-butylphosphinic acid (CGP36742 or SGS742). cis-[IC(50)(rho1) = 5.06 microM and IC(50)(rho2) = 11.08 microM; n = 4] and trans-3-ACPMPA [IC(50)(rho1) = 72.58 microM and IC(50)(rho2) = 189.7 microM; n = 4] seem competitive at GABA(C) receptors expressed in Xenopus laevis oocytes, having no effect as agonists (1 mM) but exerting weak antagonist (1 mM) effects on human GABA(A) and GABA(B) receptors. cis-3-ACPBPA was more potent and selective than the trans-compound, being more than 100 times more potent at GABA(C) than GABA(A) or GABA(B) receptors. cis-3-ACPBPA was further evaluated on dissociated rat retinal bipolar cells and dose-dependently inhibited the native GABA(C) receptor (IC(50) = 47 +/- 4.5 microM; n = 6). When applied to the eye as intravitreal injections, cis- and trans-3-ACPBPA prevented experimental myopia development and inhibited the associated vitreous chamber elongation, in a dose-dependent manner in the chick model. Doses only 10 times greater than required to inhibit recombinant GABA(C) receptors caused the antimyopia effects. Using intraperitoneal administration, cis- (30 mg/kg) and trans-3-ACPBPA (100 mg/kg) enhanced learning and memory in male Wistar rats; compared with vehicle there was a significant reduction in time for rats to find the platform in the Morris water maze task (p < 0.05; n = 10). As the physiological effects of cis- and trans-3-ACPBPA are similar to those reported for CGP36742, the memory and refractive effects of CGP36742 may be due in part to its GABA(C) activity.
Abdel-Halim,
A molecular basis for agonist and antagonist actions at GABA(C) receptors.
2008, Pubmed
Abdel-Halim,
A molecular basis for agonist and antagonist actions at GABA(C) receptors.
2008,
Pubmed
Alakuijala,
Evidence for a functional role of GABA receptors in the rat mature hippocampus.
2006,
Pubmed
Arnaud,
Study of a GABAC receptor antagonist on sleep-waking behavior in rats.
2001,
Pubmed
Bormann,
The 'ABC' of GABA receptors.
2000,
Pubmed
Boue-Grabot,
Molecular and electrophysiological evidence for a GABAc receptor in thyrotropin-secreting cells.
2000,
Pubmed
Boue-Grabot,
Expression of GABA receptor rho subunits in rat brain.
1998,
Pubmed
Bullock,
SGS-742 Novartis.
2005,
Pubmed
Chebib,
Unsaturated phosphinic analogues of gamma-aminobutyric acid as GABA(C) receptor antagonists.
1997,
Pubmed
,
Xenbase
Chebib,
(3-Aminocyclopentyl)methylphosphinic acids: novel GABA(C) receptor antagonists.
2007,
Pubmed
,
Xenbase
Chebib,
GABA-Activated ligand gated ion channels: medicinal chemistry and molecular biology.
2000,
Pubmed
Chebib,
The effects of cyclopentane and cyclopentene analogues of GABA at recombinant GABA(C) receptors.
2001,
Pubmed
,
Xenbase
Deschaux,
Influence of a GABA(B) and GABA(C) receptor antagonist on sleep-waking cycle in the rat.
2006,
Pubmed
Duke,
(+)- and (-)-cis-2-aminomethylcyclopropanecarboxylic acids show opposite pharmacology at recombinant rho(1) and rho(2) GABA(C) receptors.
2000,
Pubmed
,
Xenbase
Euler,
Different contributions of GABAA and GABAC receptors to rod and cone bipolar cells in a rat retinal slice preparation.
1998,
Pubmed
Froestl,
Phosphinic acid analogues of GABA. 2. Selective, orally active GABAB antagonists.
1995,
Pubmed
Gibbs,
Opposing roles for GABAA and GABAC receptors in short-term memory formation in young chicks.
2005,
Pubmed
Hanrahan,
Diastereoselective synthesis of (+/-)-(3-aminocyclopentane)alkylphosphinic acids, conformationally restricted analogues of GABA.
2006,
Pubmed
Helm,
GABAB receptor antagonist SGS742 improves spatial memory and reduces protein binding to the cAMP response element (CRE) in the hippocampus.
2005,
Pubmed
Irwin,
Comprehensive observational assessment: Ia. A systematic, quantitative procedure for assessing the behavioral and physiologic state of the mouse.
1968,
Pubmed
Johnston,
GABA(C) receptors as drug targets.
2003,
Pubmed
Krehan,
Phosphinic, phosphonic and seleninic acid bioisosteres of isonipecotic acid as novel and selective GABA(C) receptor antagonists.
2003,
Pubmed
,
Xenbase
Lummis,
A cation-pi binding interaction with a tyrosine in the binding site of the GABAC receptor.
2005,
Pubmed
Marshall,
GABAB receptors - the first 7TM heterodimers.
1999,
Pubmed
Mondadori,
CGP 36742: the first orally active GABAB blocker improves the cognitive performance of mice, rats, and rhesus monkeys.
1993,
Pubmed
Qian,
GABAA and GABAC receptors on hybrid bass retinal bipolar cells.
1995,
Pubmed
Ragozzino,
Design and in vitro pharmacology of a selective gamma-aminobutyric acidC receptor antagonist.
1996,
Pubmed
,
Xenbase
Ramsey,
An electrophysiological study of retinal function in the diabetic female rat.
2006,
Pubmed
Rozzo,
Antagonism by (1,2,5,6-tetrahydropyridine-4-yl) methylphosphinic acid of synaptic transmission in the neonatal rat spinal cord in vitro: an electrophysiological study.
1999,
Pubmed
Schmid,
Inhibitory effects of apomorphine and atropine and their combination on myopia in chicks.
2004,
Pubmed
Schmid,
Effects on the compensatory responses to positive and negative lenses of intermittent lens wear and ciliary nerve section in chicks.
1996,
Pubmed
Schmid,
The effect of manipulations to target contrast on emmetropization in chick.
2006,
Pubmed
Song,
The GABA rho1 subunit interacts with a cellular retinoic acid binding protein in mammalian retina.
2005,
Pubmed
Stone,
GABA, experimental myopia, and ocular growth in chick.
2003,
Pubmed
Wallman,
Subcortical optokinetic mechanisms.
1993,
Pubmed
Yang,
GABAC receptor agonist suppressed ammonia-induced apoptosis in cultured rat hippocampal neurons by restoring phosphorylated BAD level.
2003,
Pubmed
