8-Substituted Triazolobenzodiazepines: and Pharmacology in Relation to Structural Docking at the α1 Subunit-Containing GABA Receptor.

In order to develop improved anxiolytic drugs, 8-substituted analogs of triazolam were synthesized in an effort to discover compounds with selectivity for α2/α3 subunit-containing GABA subtypes. Two compounds in this series, XLi-JY-DMH (6-(2-chlorophenyl)-8-ethynyl-1-methyl-4H-benzo [f][1,2,4]triazolo[4,3-a][1,4]diazepine) and SH-TRI-108 [(E)-8-ethynyl-1-methyl-6-(pyridin-2-yl)-4H-benzo [f][1,2,4]triazolo[4,3-a][1,4]diazepine], were evaluated for and properties associated with GABA subtype-selective ligands. In radioligand binding assays conducted in transfected HEK cells containing rat αXβ3γ2 subtypes (X = 1,2,3,5), no evidence of selectivity was obtained, although differences in potency relative to triazolam were observed overall (triazolam > XLi-JY-DMH > SH-TRI-108).

The GABAA receptor alpha+beta- interface: a novel target for subtype selective drugs.

GABA(A) receptors mediate the action of many clinically important drugs interacting with different binding sites. For some potential binding sites, no interacting drugs have yet been identified. Here, we established a steric hindrance procedure for the identification of drugs acting at the extracellular α1+β3- interface, which is homologous to the benzodiazepine binding site at the α1+γ2- interface.

Anxiolytic-like effects of 8-acetylene imidazobenzodiazepines in a rhesus monkey conflict procedure.

Conflict procedures can be used to study the receptor mechanisms underlying the anxiolytic effects of benzodiazepines and other GABA(A) receptor modulators. In the present study, we first determined the efficacy and binding affinity of the benzodiazepine diazepam and recently synthesized GABA(A) receptor modulators JY-XHe-053, XHe-II-053, HZ-166, SH-053-2'F-S-CH₃ and SH-053-2'F-R-CH₃ at GABA(A) receptors containing α1, α2, α3 and α5 subunits. Results from these studies suggest that each compound displayed lower efficacy at GABA(A) receptors containing α1 subunits and varying degrees of efficacy and affinity at GABA(A) receptors containing α2, α3 and α5 subunits.

The point mutation gamma 2F77I changes the potency and efficacy of benzodiazepine site ligands in different GABAA receptor subtypes.

Benzodiazepine site agonists or inverse agonists enhance or reduce gamma-aminobutyric acid(A) (GABA(A)) receptor-mediated inhibition of neurons, respectively. Recently, it was demonstrated that the point mutation gamma 2F77I causes a drastic change in the affinity of a variety of benzodiazepine agonists or inverse agonists in receptor binding studies. Here we investigated the potency and efficacy of 10 benzodiazepine site ligands from 6 structural classes in wild-type and gamma 2F77I point mutated recombinant GABA(A) receptors composed of alpha 1 beta 3 gamma 2, alpha 2 beta 3 gamma 2, alpha 3 beta 3 gamma 2, alpha 4 beta 3 gamma 2, alpha 5 beta 3 gamma 2, and alpha 6 beta 3 gamma 2 subunits.

Antiseizure activity of novel gamma-aminobutyric acid (A) receptor subtype-selective benzodiazepine analogues in mice and rat models.

The antiseizure activity of benzodiazepines (BDZs) 1-5 in mice and rats as animal models is described. These BDZs have selective efficacy for alpha2beta3gamma2 and alpha3beta3gamma2 GABA(A)-receptors. Significant anticonvulsant activity with little or no motor impairment and therapeutic indexes (TI) of 2.

A study of the structure-activity relationship of GABA(A)-benzodiazepine receptor bivalent ligands by conformational analysis with low temperature NMR and X-ray analysis.

The stable conformations of GABA(A)-benzodiazepine receptor bivalent ligands were determined by low temperature NMR spectroscopy and confirmed by single crystal X-ray analysis. The stable conformations in solution correlated well with those in the solid state. The linear conformation was important for these dimers to access the binding site and exhibit potent in vitro affinity and was illustrated for alpha5 subtype selective ligands.

Selective influence on contextual memory: physiochemical properties associated with selectivity of benzodiazepine ligands at GABAA receptors containing the alpha5 subunit.

Ligands that bind to the benzodiazepine binding site on the GABA A receptor can attenuate or potentiate cognition. To investigate this property, the chemical determinants favoring selective binding or selective activation of the alpha5beta2gamma2 and alpha1beta2gamma2 GABA A receptor isoforms were examined. A 3D-pharmacophore, developed from a diverse set of BDZR ligands, was used as an initial basis for multivariate discriminant, fragment, and 3D-quantitative structure-activity relationship analyses, which formed the criteria for selection of additional compounds for study.

Are GABAA receptors containing alpha5 subunits contributing to the sedative properties of benzodiazepine site agonists?

Classical benzodiazepines (BZs) exert anxiolytic, sedative, hypnotic, muscle relaxant, anticonvulsive, and amnesic effects through potentiation of neurotransmission at GABA(A) receptors containing alpha(1), alpha(2), alpha(3) or alpha(5) subunits. Genetic studies suggest that modulation at the alpha(1) subunit contributes to much of the adverse effects of BZs, most notably sedation, ataxia, and amnesia. Hence, BZ site ligands functionally inactive at GABA(A) receptors containing the alpha(1) subunit are considered to be promising leads for novel, anxioselective anxiolytics devoid of sedative properties.

N-Substituted 4-amino-3,3-dipropyl-2(3H)-furanones: new positive allosteric modulators of the GABA(A) receptor sharing electrophysiological properties with the anticonvulsant loreclezole.

1,4-Addition of benzylamine to 2(5H)-furanone followed by dialkylation of the 3-position with allylbromide gave (+/-)-4-benzyl-3,3-diallyl-2(3H)-furanone (8), which served as the intermediate for the synthesis of various N-substituted 4-amino-3,3-dipropyl-2(3H)-furanones (+/-)-9a-l. The compounds were evaluated for their capacity to potentiate or inhibit GABA-evoked currents in Xenopus laevis oocytes expressing recombinant alpha1beta2gamma2 GABA(A) receptors. The benzyl, ethyl, and allyl carbamates ((R)-9a (100 microM), (+/-)-9b (100 microM), (+/-)-9c (200 microM)) stimulated GABA currents by 279 +/- 47%, 426 +/- 8%.

Tranexamic acid, a widely used antifibrinolytic agent, causes convulsions by a gamma-aminobutyric acid(A) receptor antagonistic effect.

Application of 4-(aminomethyl)cyclohexanecarboxylic acid (tranexamic acid; TAMCA) to the central nervous system (CNS) has been shown to result in hyperexcitability and convulsions. However, the mechanisms underlying this action are unknown. In the present study, we demonstrate that TAMCA binds to the gamma-aminobutyric acid (GABA) binding site of GABA(A) receptors in membranes from rat cerebral cortex and does not interfere with N-methyl-D-aspartate receptors.