A 2-week efficacy and safety study of gaboxadol and zolpidem using electronic diaries in primary insomnia outpatients.

Objectives: To evaluate the efficacy and safety profile of gaboxadol, a selective extrasynaptic GABA(A) agonist (SEGA) previously in development for the treatment of insomnia.

Methods: This was a randomised, double-blind, placebo-controlled, parallel-group, 2-week, Phase III study of gaboxadol 5, 10 and 15mg in outpatients meeting the DSM-IV criteria of primary insomnia (N=742). Zolpidem 10mg was used as active reference.

4-aryl-5-(4-piperidyl)-3-isoxazolol GABAA antagonists: synthesis, pharmacology, and structure-activity relationships.

A series of 4-aryl-5-(4-piperidyl)-3-isoxazolol GABAA antagonists have been synthesized and pharmacologically characterized. The meta-phenyl-substituted compounds 9k and 9m and the para-phenoxy-substituted compound 9l all display high affinities (Ki=10-70 nM) and antagonist potencies in the low nanomolar range (Ki=9-10 nM). These potencies are significantly higher than those of previously reported 4-PIOL antagonists and considerably higher than that of the standard GABAA antagonist SR 95531.

Depression and poor sleep: the effect of monoaminergic antidepressants in a pre-clinical model in rats.

The effects of five antidepressants (escitalopram, paroxetine, duloxetine, venlafaxine, and reboxetine) on the sleep architecture were investigated in freely moving rats in the light phase of a 12:12 h light:dark cycle following a single i.p. dose of antidepressant.

Potent 4-arylalkyl-substituted 3-isothiazolol GABA(A) competitive/noncompetitive antagonists: synthesis and pharmacology.

The GABA(A) agonists muscimol (1), 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, gaboxadol, 3), and the partial GABA(A) agonist 5-(4-piperidyl)-3-isoxazolol (4-PIOL, 6a) and their respective 3-isothiazolol analogues thiomuscimol (2), thio-THIP (4), and thio-4-PIOL (7a) are ligands at the GABA(A) orthosteric (recognition) site. The structure-activity relationships (SARs) between these structures are key elements of a 3D-pharmacophore model for GABA(A) agonists and competitive antagonists [Frølund, B.; Jørgensen, A.

Pharmacological characterization of agonists at delta-containing GABAA receptors: Functional selectivity for extrasynaptic receptors is dependent on the absence of gamma2.

Several groups have characterized the pharmacology of alpha4- or alpha6beta3delta-containing GABA(A) receptors expressed in different cell systems. We have previously demonstrated that the pharmacological profiles of a series of GABA(A) receptor agonists are highly dependent on the alpha subunit and little on the beta and gamma subunits, so to further understand the contribution of the different subunits in the GABA(A) receptor complex, we characterized a series of full agonists, partial agonists, and antagonists at alpha4beta3, alpha4beta3delta, and alpha6beta3delta receptors expressed in Xenopus oocytes. Little or no difference was seen when the compounds were compared at alphabeta- and alphabetadelta-containing receptors, whereas a significant reduction in both potency and relative efficacy was observed compared with alphabetagamma-containing receptors described in the literature.

The delta subunit of gamma-aminobutyric acid type A receptors does not confer sensitivity to low concentrations of ethanol.

GABA(A) receptors (GABA(A)Rs) are usually formed by alpha, beta, and gamma or delta subunits. Recently, delta-containing GABA(A)Rs expressed in Xenopus oocytes were found to be sensitive to low concentrations of ethanol (1-3 mM). Our objective was to replicate and extend the study of the effect of ethanol on the function of alpha4beta3delta GABA(A)Rs.

R-citalopram functionally antagonises escitalopram in vivo and in vitro: evidence for kinetic interaction at the serotonin transporter.

1. Clinical observations with the selective serotonin reuptake inhibitor (SSRI), S-citalopram, indicate that S-citalopram is more efficacious and produces earlier symptom relief than RS-citalopram. Since R-citalopram is at least 20-fold weaker than S-citalopram as inhibitor of the 5-HT transporter (SERT) in preclinical studies, the clinical data suggest an unexpected antagonistic interaction between the two enantiomers.

Gaboxadol: in vitro interaction studies with benzodiazepines and ethanol suggest functional selectivity.

The interaction of gaboxadol (THIP; 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol), ethanol and a series of benzodiazepine site agonists including diazepam, flunitrazepam, lorazepam, indiplon, zaleplon and zolpidem has been characterized at human alpha(1)beta(3)gamma(2S) gamma-aminobutyric acid type A (GABA(A)) receptors expressed in Xenopus oocytes and in the rat cortical wedge preparation. At the expressed receptors, gaboxadol and the benzodiazepine site agonists interacted synergistically and ethanol did not further enhance this potentiation. In contrast, in the rat cortical wedge preparation, where the inhibition of spontaneous activity was assessed, much weaker effects of the benzodiazepine site agonists were seen.