A novel positive allosteric modulator of the GABA(A) receptor: The action of (+)-ROD188

Department of Pharmacology, University of Bern, CH-3010 Bern, Switzerland.
British Journal of Pharmacology (Impact Factor: 4.84). 10/2000; 131(4):843-50. DOI: 10.1038/sj.bjp.0703558
Source: PubMed


(+)-ROD188 was synthesized in the search for novel ligands of the GABA binding site. It shares some structural similarity with bicuculline. (+)-ROD188 failed to displace [(3)H]-muscimol in binding studies and failed to induce channel opening in recombinant rat alpha1beta2gamma2 GABA(A) receptors functionally expressed in Xenopus oocytes. (+)-ROD188 allosterically stimulated GABA induced currents. Displacement of [(3)H]-Ro15-1788 indicated a low affinity action at the benzodiazepine binding site. In functional studies, stimulation by (+)-ROD188 was little sensitive to the presence of 1 microM of the benzodiazepine antagonist Ro 15-1788, and (+)-ROD188 also stimulated currents mediated by alpha1beta2, indicating a major mechanism of action different from that of benzodiazepines. Allosteric stimulation by (+)-ROD188 was similar in alpha1beta2N265S as in unmutated alpha1beta2, while that by loreclezole was strongly reduced. (+)-ROD188 also strongly stimulated currents elicited by either pentobarbital or 5alpha-pregnan-3alpha-ol-20-one (3alpha-OH-DHP), in line with a mode of action different from that of barbiturates or neurosteroids as channel agonists. Stimulation by (+)-ROD188 was largest in alpha6beta2gamma2 (alpha6beta2gamma2>alpha1beta2gamma2=alpha5beta2gamma2++ +>alpha2beta2ga mma2= alpha3beta2gamma2), indicating a unique subunit isoform specificity. Miniature inhibitory postsynaptic currents (mIPSC) in cultures of rat hippocampal neurons, caused by spontaneous release of GABA showed a prolonged decay time in the presence of 30 microM (+)-ROD188, indicating an enhanced synaptic inhibitory transmission.

Download full-text


Available from: Werner Sieghart,
  • Source
    • "Some other compounds interacting with ab receptors have already been excluded as possible ligands for the CGS 9895 binding site. Thus, the additional GABA-potentiating effect at 100 mM diazepam in a1bg2 receptors (Walters et al., 2000) or the effect of 10 mM ROD 188 (Thomet et al., 2000) on a1b3 receptors could not be inhibited by the steric hindrance approach under conditions where the effects of CGS 9895 were completely abolished (Ramerstorfer et al., 2011). Further experiments have to clarify, whether the effects of for instance Valerenic acid (Khom et al., 2010; Kopp et al., 2010) or of some flavonoids (Hanrahan et al., 2011) on a1b3 receptors are mediated via the CGS 9895 binding site. "
    [Show abstract] [Hide abstract]
    ABSTRACT: GABA(A) receptors are ligand-gated chloride channels composed of five subunits that can belong to different subunit classes. The existence of 19 different subunits gives rise to a multiplicity of GABA(A) receptor subtypes with distinct subunit composition; regional, cellular and subcellular distribution; and pharmacology. Most of these receptors are composed of two α, two β and one γ2 subunits. GABA(A) receptors are the site of action of a variety of pharmacologically and clinically important drugs, such as benzodiazepines, barbiturates, neuroactive steroids, anaesthetics and convulsants. Whereas GABA acts at the two extracellular β(+) α(-) interfaces of GABA(A) receptors, the allosteric modulatory benzodiazepines interact with the extracellular α(+) γ2(-) interface. In contrast, barbiturates, neuroactive steroids and anaesthetics seem to interact with solvent accessible pockets in the transmembrane domain. Several benzodiazepine site ligands have been identified that selectively interact with GABA(A) receptor subtypes containing α2βγ2, α3βγ2 or α5βγ2 subunits. This indicates that the different α subunit types present in these receptors convey sufficient structural differences to the benzodiazepine binding site to allow specific interaction with certain benzodiazepine site ligands. Recently, a novel drug binding site was identified at the α(+) β(-) interface. This binding site is homologous to the benzodiazepine binding site at the α(+) γ2(-) interface and is thus also strongly influenced by the type of α subunit present in the receptor. Drugs interacting with this binding site cannot directly activate but only allosterically modulate GABA(A) receptors. The possible importance of such drugs addressing a spectrum of receptor subtypes completely different from that of benzodiazepines is discussed.
    British Journal of Pharmacology 11/2011; 166(2):476-85. DOI:10.1111/j.1476-5381.2011.01779.x · 4.84 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: GABAC receptors are expressed in the whole brain, but predominantly in the retina. They can be identified by their unique pharmacology. The establishment of the entire pharmacology is, however, quite tedious. We show here that loreclezole dose dependently inhibits ionic currents elicited by GABA (γ-aminobutyric acid) with an IC50 of about 0.5 μM in homomeric ρ1 GABAC receptors expressed in Xenopus oocytes. Thus, loreclezole may constitute a functional marker for these receptors.
    European Journal of Pharmacology 11/2000; 408(2-408). DOI:10.1016/S0014-2999(00)00778-0 · 2.53 Impact Factor

  • Drugs of the Future 12/2001; 26(12). DOI:10.1358/dof.2001.026.12.639536 · 0.17 Impact Factor
Show more