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Molecular and Neurochemical Evaluation of the Effects of Etizolam on GABAA Receptors under Normal an

Molecular and Neurochemical Evaluation of the Effects of Etizolam on GABAA Receptors under Normal an

  1. Calliope
    Arzneimittel-Forschung [serial online]. February 1999;49(2):88-95.
    PMID 10083975

    Enrico Sanna, Davide Pau, Francesca Tuveri, Federico Massa, Elisabetta Maciocco, Cinzia Acquas, Chiara Floris, Simona N. Fontana, Giovanna Maira, Giovanni Biggio

    Abstract
    The thienobenzodiazepine derivative etizolam (CAS 40054-69-1, 6-(o-chlorophenyl)-8-ethyl-1-methyl-4H-s-triazolo-(3,4-c)thienol (1,4)diazepine) is a potent anxiolytic with a pharmacological profile similar to that of classical benzodiazepines. In order to rationalize the therapeutic use of etizolam, its pharmacodynamics properties on GABAA receptors were investigated by a comparative study with other ligands on human recombinant GABAA as well as rat brain native receptors. Etizolam inhibited in a concentration-dependent manner [3H]flunitrazepam (CAS 1622-62-4) binding to rat cortical membranes, with an affinity of 4.5 nmol/l greater than
    that of alprazolam (CAS 28981-97-7) (7.9 nmol/l). Ethizolam enhanced GABA-induced Clcurrents in oocytes expressing human cloned GABAA receptors. With a1b2g2S subunit combination, etizolam produced a 73 % increase in GABA-induced currents with an EC50 of 92 nmol/l. At the same receptor type, alprazolam showed a higher degree of potentiation and potency (98 %, EC50 56 nmol/l). At a2b2g2S or a3b2g2S subunit constructs, the effects of etizolam were similar to those of alprazolam. Flumazenil (CAS 78755-81-4) completely blocked both etizolam and alprazolam effects on GABA-induced currents. Etizolam, administered i.p., was ineffective in changing ex vivo t-[35S]butylbicyclophosphorothionate ([35S]-TBPS) binding to rat cerebral cortex, whereas alprazolam and abecarnil (CAS 111841-85-1) significantly reduced this parameter. However, etizolam similarly to abecarnil and alprazolam, antagonized isoniazid-induced increase (61 %) in [35S]-TBPS binding to rat cortical membranes. Further, etizolam inhibited in a dose-dependent manner basal acetylcholine release from both hippocampus and prefrontal cortex, and reversed foot-shock-induced increase of basal acetylcholine release to a control level. Altogether, these results suggest that etizolam may have a reduced intrinsic activity, at least at specific subpopulations of GABAA receptors. This property, together with the pharmacokinetic indication of a short-acting drug, may characterize etizolam as a ligand endowed with less side-effects typical of full agonits such as diazepam (CAS 439-14-5) and alprazolam. Finally, given its marked efficacy under conditions of GABAergic deficit, etizolam may represent a possible drug of choice with reduced liability to produce tolerance and dependence after long-term treatment of anxiety and stress syndromes.