Novel, Potent, and Selective GABA_CAntagonists Inhibit Myopia Development and Facilitate Learning and Memory

Abstract

This study reports pharmacological and physiological effects of cis-and trans-(3-aminocyclopentanyl)butylphosphinic acid . 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 (1) ϭ 5.06 M and IC 50 (2) ϭ 11.08 M; n ϭ 4] and trans-3-ACPMPA [IC 50 (1) ϭ 72.58 M and IC 50 (2) ϭ 189.7 M; n ϭ 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 ϭ 47 Ϯ 4.5 M; n ϭ 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 Ͻ 0.05; n ϭ 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.GABA is an abundant neurotransmitter that mediates inhibition throughout the retina and central nervous system. Three main classes of GABA receptors exist and are termed GABA A , GABA B , and GABA C receptors (Bormann, 2000;Chebib and Johnston, 2000). The GABA A and GABA C are ionotropic receptors, belonging to the Cys-loop family of ligand-gated ion channels, which includes nicotinic acetylcholine, strychnine-sensitive glycine, serotonin type 3, and some invertebrate anionic glutamate receptors (Bormann, 2000;Chebib and Johnston, 2000). Both GABA A and GABA C receptors are chloride channels that mediate fast synaptic inhibition when activated by GABA. In contrast, GABA B receptors are members of the metabotropic receptor family; these receptors couple via G proteins (G i/o ) to interact with neuronal inwardly rectifying potassium and voltage-gated calcium channels, mediating slow synaptic inhibition by increasing 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 ...

Antagonists of Ionotropic Receptors for the Inhibitory Neurotransmitter GABA: Therapeutic Indications

“…GABA C receptor antagonists have also been useful experimental tools for demonstrating a role for these receptors in learning and memory [49,50,54]. TPMPA and the structural analog P4MPA ((piperidin-4-yl)methylphosphinic acid) were shown to enhance short-term memory in a bead discrimination task following injection into the multimodal association forebrain area in chicks [49].…”

“…form-deprivation myopia [51], while (3-aminopropyl)-n-butylphosphinic acid (CGP36742 or SGS742) was found to inhibit the development of myopia in chicks [50]. Thus, TPMPA and related GABA C receptor antagonists have been suggested for the treatment of myopia, administered intravitreally, orally, and ophthalmically [52].…”

“…TPMPA and other GABA C receptor antagonists have been used to demonstrate the important role of GABA C receptors in many aspects of vision [50][51][52][53]. TPMPA was shown to inhibit …”

Novel Cyclic Phosphinic Acids as GABAC ρ Receptor Antagonists: Design, Synthesis, and Pharmacology

“…In continuation of our efforts to identify the role of GABA C receptors in the CNS, we discovered that the selective GABA C receptor antagonists, cis-and trans-(3-aminocyclopentanyl)-n-butylphosphinic acid (cis-3-ACPBPA 4 and trans-3-ACPBPA 5; Figure 1), inhibit myopia progression in chicks and facilitate learning and memory in the Morris Water Maze task in rats. 19 The discovery of potent and selective GABA C antagonists emphasizes some important pharmacological differences between these GABA receptor families. Thus, GABA C receptors may be of clinical and pharmacological interest as potential therapeutic targets for myopia, in enhancing cognition and managing memory-related disorders, and its presence in the amygdala might be an alternative target for the development of antianxiety drugs.…”

Graham Johnston: Bringing Success to Neuroscience Through Medicinal Chemistry

“…We cannot but speculate whether Graham's continued interest in the actions of therapeutically beneficial, dietary flavonoids at the GABA A receptor is fuelled by a love of fine food and wine [6,7]. More recently his work has led to the definition of the GABA C receptor [8], which appears to represent a therapeutic target for myopia and in enhancing cognition and in managing memory-related disorders [9]. Other early studies showed the way towards defining the multiple subtypes of ionotropic receptors for L-glutamate [10,11].…”