Faculty Collaboration Database

Further evaluation of the potential anxiolytic activity of imidazo[1,5-a][1,4]diazepin agents selective for α2/3-containing GABA_A receptors. Pharmacol Biochem Behav 2017 Jun;157:35-40

Date

04/27/2017

Pubmed ID

28442369

Pubmed Central ID

PMC5519285

DOI

10.1016/j.pbb.2017.04.009

Scopus ID

2-s2.0-85019841584 (requires institutional sign-in at Scopus site)   22 Citations

Abstract

Positive allosteric modulators of GABA_A receptors transduce a host of beneficial effects including anxiolytic actions. We have recently shown that bioavailability and anxiolytic-like activity can be improved by eliminating the ester functionality in imidazo[1,5-a][1,4]diazepines. In the present series of experiments, we further substantiate the value of heterocyle replacement of the ester for potential treatment of anxiety. None of three esters was active in a Vogel conflict test in rats that detects anxiolytic drugs like diazepam. Compounds 7 and 8, ester bioisosters, were selective for alpha 2 and 3 over alpha 1-containing GABA_A receptors but also had modest efficacy at GABAA alpha 5-containing receptors. Compound 7 was efficacious and potent in this anxiolytic-detecting assay without affecting non-punished responding. The efficacies of the esters and of compound 7 were predicted from their efficacies as anticonvulsants against the GABA_A antagonist pentylenetetrazole (PTZ). In contrast, the related structural analog, compound 8, did not produce anxiolytic-like effects in rats despite anticonvulsant efficacy. These data thus support the following conclusions: 1) ancillary pharmacological actions of compound 8 might be responsible for its lack of anxiolytic-like efficacy despite its efficacy as an anticonvulsant 2) esters of imidazo[1,5-a][1,4]diazepines do not demonstrate anxiolytic-like effects in rats due to their low bioavailability and 3) replacement of the ester function with suitable heterocycles markedly improves bioavailability and engenders molecules with the opportunity to have potent and efficacious effects in vivo that correspond to human anxiolytic actions.

Author List

Witkin JM, Cerne R, Wakulchik M, S J, Gleason SD, Jones TM, Li G, Arnold LA, Li JX, Schkeryantz JM, Methuku KR, Cook JM, Poe MM

Authors

Alexander (Leggy) Arnold PhD Professor in the Chemistry & Biochemistry department at University of Wisconsin - Milwaukee
James M. Cook PhD University Distinguished Professor in the Chemistry and Biochemistry department at University of Wisconsin - Milwaukee

MESH terms used to index this publication - Major topics in bold

Animals
Anti-Anxiety Agents
Anxiety
Benzodiazepines
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
GABA-A Receptor Agonists
HEK293 Cells
Humans
Male
Rats
Rats, Sprague-Dawley
Receptors, GABA-A