Novel, potent, and selective GABAC antagonists inhibit myopia development and facilitate learning and memory

Chebib, Mary, Hinton, Tina, Schmid, Katrina L., Brinkworth, Darren, Qian, Haohua, Matos, Susana, Kim, Hye-Lim, Abdel-Halim, Heba, Kumar, Rohan J., Johnston, Graham A. R., & Hanrahan, Jane R. (2008) Novel, potent, and selective GABAC antagonists inhibit myopia development and facilitate learning and memory. Journal of Pharmacology and Experimental Therapeutics, 328(2), pp. 448-457.

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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 GABAB/C receptor antagonist (3-aminopropyl)-n-butylphosphinic acid (CGP36742 or SGS742). cis-[IC50(1) = 5.06 µM and IC50(2) = 11.08 µM; n = 4] and trans-3-ACPMPA [IC50(1) = 72.58 µM and IC50(2) = 189.7 µM; n = 4] seem competitive at GABAC receptors expressed in Xenopus laevis oocytes, having no effect as agonists (1 mM) but exerting weak antagonist (1 mM) effects on human GABAA and GABAB receptors. cis-3-ACPBPA was more potent and selective than the trans-compound, being more than 100 times more potent at GABAC than GABAA or GABAB receptors. cis-3-ACPBPA was further evaluated on dissociated rat retinal bipolar cells and dose-dependently inhibited the native GABAC receptor (IC50 = 47 ± 4.5 µM; 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 GABAC 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 GABAC activity.

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ID Code: 18839
Item Type: Journal Article
Refereed: Yes
Additional Information: All articles after 12 months back to 1 Jan 1997
Additional URLs:
Keywords: GABA receptors, GABA-C antagonists, Morris water maze, Electrophysiology, Memory, Myopia
DOI: 10.1124/jpet.108.146464
ISSN: 0022-3565
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > OPTOMETRY AND OPHTHALMOLOGY (111300) > Vision Science (111303)
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Deposited On: 11 May 2009 02:45
Last Modified: 06 Jul 2017 14:01

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