Ester to amide substitution improves selectivity, efficacy and kinetic behavior of a benzodiazepine positive modulator of GABA(A) receptors containing the alpha 5 subunit
Poe, Michael M.
Cook, James M.
Article (Published version)
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We have synthesized and characterized MP-III-022 ((R)-8-ethynyl 6 (2 fluorophenyl)-N,4-dimethyl4H-benzo[f]imidazo[1,5-alpha][1,4]diazepine-3-carboxamide) in vitro and in vivo as a binding- and efficacy selective positive allosteric modulator of GABA(A) receptors containing the alpha 5 subunit (alpha 5GABA(A)Rs). By approximation of the electrophysiological responses which the estimated free rat brain concentrations can induce, we demonstrated that convenient systemic administration of MP-III-022 in the dose range 110 mg/kg may result in a selective potentiation, over a wide range from mild to moderate to strong, of alpha 5 beta gamma 2 GABA(A) receptors. For eliciting a comparable range of potentiation, the widely studied parent ligand SH-053-2'F-R-CH3 containing an ester moiety needs to be administered over a much wider dose range (10-200 mg/kg), but at the price of activating non-alpha 5 GABA(A)Rs as well as the desired alpha 5GABA(A)Rs at the highest dose. At the dose of 10 mg/kg, w...hich elicits a strong positive modulation of alpha 5GABA(A)Rs, MP-III-022 caused mild, but significant muscle relaxation, while at doses 1-10 mg/kg was devoid of ataxia, sedation or an influence on the anxiety level, characteristic for non-selective benzodiazepines. As an amide compound with improved stability and kinetic properties, MP-III-022 may represent an optimized tool to study the influence of alpha 5GABA(A)Rs on the neuronal pathways related to CNS disorders such as schizophrenia, Alzheimer's disease, Down syndrome or autism.
Source:European Journal of Pharmacology, 2016, 791, 433-443
- Elsevier Science BV, Amsterdam