There has been a resurgence of interest in synthetic and plant-derived flavonoids as modulators of g-amino butyric acid-A (GABAA) receptor function influencing inhibition mediated by the major inhibitory neurotransmitter GABA in the brain. Areas of interest include (i) flavonoids that show subtype selectivity in recombinant receptor studies in vitro consistent with their behavioural effects in vivo, (ii) flumazenil-insensitive modulation of GABAA receptor function by flavonoids, (iii) the ability of some flavonoids to act as second-order modulators of first-order modulation by benzodiazepines and (iv) the identification of the different sites of action of flavonoids on GABAA receptor complexes. An emerging area of interest is the activation of GABAA receptors by flavonoids in the absence of GABA. The relatively rigid shape of flavonoids means that they are useful scaffolds for the design of new therapeutic agents. Like steroids, flavonoids have wide-ranging effects on numerous biological targets. The challenge is to understand the structural determinants of flavonoid effects on particular targets and to develop agents specific for these targets.

GABAA receptors are members of the ligand-gated ion channel superfamily that mediate inhibitory neurotransmission in the central nervous system. They are thought to be composed of 2 alpha (α), 2 beta (β) subunits and one other such as a gamma (γ) or delta (δ) subunit. The potency of GABA is influenced by the subunit composition. However, there are no reported systematic studies that evaluate GABA potency on a comprehensive number of subunit combinations expressed in Xenopus oocytes, despite the wide use of this heterologous expression system in structure-function studies and drug discovery. Thus, the aim of this study was to conduct a systematic characterization of the potency of GABA at 43 human recombinant GABA(A) receptor combinations expressed in Xenopus oocytes using the two-electrode voltage clamp technique. The results show that the α-subunits and to a lesser extent, the β-subunits influence GABA potency. Of the binary and ternary combinations with and without the γ2L subunit, the α6/γ2L-containing receptors were the most sensitive to GABA, while the β2- or β3-subunit conferred higher sensitivity to GABA than receptors containing the β1-subunit with the exception of the α2β1γ2L and α6β1γ2L subtypes. Of the δ-subunit containing GABA(A) receptors, α4/δ-containing GABA(A) receptors displayed highest GABA sensitivity, with mid-nanomolar concentrations activating α4β1δ and α4β3δ receptors. At α4β2δ, GABA had low micromolar activity.

GABA(C) receptors are the least studied of the three major classes of GABA receptors. The physiological roles of GABA(C) receptors are still being unravelled and the pharmacology of these receptors is being developed. A range of agents has been described that act on GABA(C) receptors with varying degrees of specificity as agonists, partial agonists, antagonists and allosteric modulators. Pharmacological differences are known to exist between subtypes of cloned GABA(C) receptors that have been cloned from mammalian sources. There is evidence for functional GABA(C) receptors in the retina, spinal cord, superior colliculus, pituitary and gastrointestinal tract. Given the lower abundance and less widespread distribution of GABA(C) receptors in the CNS compared to GABA(A) receptors, GABA(C) receptors may be a more selective drug target than GABA(A) receptors. The major indications for drugs acting on GABA(C) receptors are in the treatment of visual, sleep and cognitive disorders. The most promising leads are THIP, a GABA(C) receptor antagonist in addition to its well known activity as a GABA(A) receptor partial agonist, which is being evaluated for sleep therapy, and CGP36742, an orally active GABA(B) and GABA(C) receptor antagonist, which enhances cognition. Analogues of THIP and CGP36742, such as aza-THIP, that are selective for GABA(C) receptors are being developed. TPMPA and related compounds such as P4MPA, PPA and SEPI are also important leads for the development of systemically active selective GABA(C) receptor antagonists.

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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 ...