Novel, Potent, and Selective GABAC Antagonists Inhibit Myopia Development and Facilitate Learning and Memory

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 328; no. 2; pp. 448 - 457
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.02.2009
• Subjects: Animals; Chick Embryo; Disease Models, Animal; GABA Antagonists - therapeutic use; Humans; Learning - drug effects; Learning - physiology; Male; Maze Learning - drug effects; Maze Learning - physiology; Memory - drug effects; Memory - physiology; Myopia - prevention & control; Neuropharmacology; Organophosphorus Compounds; Patch-Clamp Techniques; Physiological Phenomena; Rats; Receptors, GABA - drug effects; Receptors, GABA-A; Receptors, GABA-B; Structure-Activity Relationship; Xenopus laevis
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.108.146464

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 (ρ1) = 5.06 μM and IC 50 (ρ2) = 11.08 μM; n = 4] and trans -3-ACPMPA [IC 50 (ρ1) = 72.58 μM and IC 50 (ρ2) = 189.7 μM; 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 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 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.