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First published on November 4, 2008; DOI: 10.1124/jpet.108.146464
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Received for publication September 23, 2008.
Revised October 30, 2008.
Accepted for publication November 3, 2008.

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

Mary Chebib 1*, Tina Hinton 1, Katrina L Schmid 2, Darren Brinkworth 2, Haohua Qian 3, Susana Matos 1, Hye-Lim Kim 1, Heba Abdel-Halim 1, Rohan J Kumar 1, Graham A R Johnston 1, Jane R Hanrahan 4

1 The University of Sydney 2 Queensland University of Technology 3 Univ. of Illinois at Chicago 4 University of Sydney

* Address correspondence to: E-mail: maryc{at}pharm.usyd.edu.au

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 GABAB/C receptor antagonist, (3-aminopropyl)-n-butylphosphinic acid (CGP36742 or SGS742). Cis- (IC50({rho}1)=5.06µM and IC50({rho}2)=11.08µM; n=4) and trans-3-ACPMPA (IC50({rho}1)=72.58µM and IC50({rho}2)=189.7 µM; n=4) appear competitive at GABAC receptors expressed in Xenopus 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 over 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±4.5µM; 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 anti-myopia effects. Using intraperitoneal administration, cis- (30 mg/kg) and trans-3-ACPBPA (100 mg/kg) enhanced learning and memory in male Wistar rats; compared to vehicle there was a significant reduction in time for rats to find the platform in the Morris Water Maze task (n=10; p<0.05). 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.


Key words: GABA receptors, GABA-C antagonists, Morris water maze, electrophysiology, memory, myopia




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