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 Cl- currents in oocytes expressing human cloned GABAA receptors. With alpha 1 beta 2 gamma 2S 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 alpha 2 beta 2 gamma 2S or alpha 3 beta 2 gamma 2S 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 uneffective 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.