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(ρ1) = 5.06 μM and IC50(ρ2) = 11.08 μM; n = 4] and trans-3-ACPMPA [IC50(ρ1) = 72.58 μM and IC50(ρ2) = 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.
Footnotes
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This work was supported in part by the National Institutes of Health [Grant EY12028], Circadian Technologies Pty. Ltd., and the Institute of Health and Biomedical Innovation.
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This article contains data presented in part in Schmid KL, Brinkworth D, Wallace KM, Payer R, Fritsch C, and Lambrou GN (2004) The effects of GABA-B and GABA-C antagonists on myopia development in chick, in Proceedings of the 10th International Conference on Myopia; 2004 July 19–22; Cambridge, UK; and Schmid KL, Brinkworth DR, Chebib M, Hanrahan JR, and Johnston GAR (2005) A theoretical model for GABAc antagonists inhibiting myopia via the ON/OFF retinal pathway, in Proceedings of the Joint Meeting of Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists and Australasian Pharmaceutical Science Association; 2005 December; Melbourne, Australia.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.146464.
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ABBREVIATIONS: TPMPA, (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid; 3-APMPA, (3-aminopropyl)-methylphosphinic acid; cis- and trans-3-ACPMPA, cis- and trans-(3-aminocyclopentanyl)methylphosphinic acid; cis- and trans-3-ACPBPA, cis- and trans-(3-aminocyclopentanyl)butylphosphinic acid; CGP36742 or SGS742, (3-aminopropyl)-n-butylphosphinic acid; GIRK, G protein-coupled inwardly rectifying potassium channel; D, diopter.
- Received September 22, 2008.
- Accepted November 3, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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