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- [IC50(rho 1) = 5.06 mu M and IC50(rho 2) = 11.08 mu M; n = 4] and trans-3-ACPMPA [IC50(rho 1) = 72.58 mu M and IC50(rho 2) = 189.7 mu M; 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 (IC50 = 47 +/- 4.5 mu M; 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.
