Further evaluation of the potential anxiolytic activity of imidazo[1,5- a ][1,4]diazepin agents selective for α2/3-containing GABA A receptors

Abstract

Positive allosteric modulators of GABAA 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 the 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 GABAA 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 GABAA 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.

8-Substituted Triazolobenzodiazepines: In Vitro and In Vivo Pharmacology in Relation to Structural Docking at the α1 Subunit-Containing GABAA Receptor

“…) demonstrated a greater degree of intrinsic efficacy at α2/ α3GABA A subtypes relative to α1GABA A subtypes (e.g., Witkin et al, 2017;Witkin et al, 2020), although at higher concentrations this and related compounds do show at least partial intrinsic efficacy at the latter subtypes (leading to the suggested descriptor of "α2/α3GABA A subtype-preferring compounds"; Maramai et al, 2020).…”

“…Specifically, in silico determination of docking scores at the α1 subunit C-loop of less than 10 kCal/mole are predicted to result in compounds with fewer sedative-motor side effects. In context, bioisostere 8ethynyl imidazodiazepines have been shown consistently to have reduced sedative effects, yet retain preclinical effects predictive of anxiolysis, as well as anti-epilepsy and antinociceptive properties (Fischer et al, 2010;Duke et al, 2018;Witkin et al, 2017;, suggesting this strategy of compound development with imidazodiazepines to be the more viable approach.…”

“…Conventional BZs (e.g., triazolam) bind nonselectively to GABA A receptors that contain α1, α2, α3, and α5 subunits (α1GABA A , α2GABA A , α3GABA A , and α5GABA A receptors, respectively) while they do not bind appreciably to α4-and α6 subunit-containing GABA A receptors. This binding profile may be responsible for the myriad of behavioral effects produced by BZs, including a role for α1GABA A receptors in the anticonvulsant, sedative, and motor effects of BZs, a role for α2GABA A and α3GABA A receptors in the anxiolytic, anticonvulsant, antinociceptive, and myorelaxant effects of BZs, and a role for α5GABA A receptors in BZ-associated memory processes as well as anxiolytic effects (e.g., Witkin et al, 2017;Witklin et al, 2018;Witkin et al, 2020;Tudeau et al, 2020 for review, Engin et al, 2018).…”

“…Because the BZ scaffold historically has proven to be generally nontoxic with desirable pharmacokinetic properties, one approach to developing functionally selective compounds has been to identify and advance a selected group of 8-substituted triazolobenzodiazepines and imidazodiazepines (e.g., Rivas et al, 2009;Poe et al, 2016). The focus recently has been on bioisostere imidazodiazepines in a novel series of compounds with preferential intrinsic efficacy at α2/3GABA A subtypes (Poe et al, 2016;Witkin et al, 2017;Witkin et al, 2018;Witkin et al, 2020), which demonstrated robust anticonvulsant properties, anxiolytic-like effects, antinociceptive effects, but with a reduced propensity to engender sedative-motor disruptions. The present study reports data from key compounds from a series of 8-substituted analogs of triazolam.…”

Metabolism, pharmacokinetics, and anticonvulsant activity of a deuterated analog of the α2/3‐selective GABAkine KRM‐II‐81

“…KRM‐II‐81 (5‐(8‐ethynyl‐6‐(pyridin‐2‐yl)‐4H‐benzo [ f ]imidazole[1,5‐α][1,4]diazepin‐3‐yl) oxazole) is a new GABAkine (gamma aminobutyric acid A [GABA A ] receptor potentiator) with anticonvulsant, anxiolytic, and antinociceptive activity in preclinical models (Biggerstaff et al., 2020; Cerne et al., 2019; Knutson et al., 2020; Lewter et al., 2017; Poe et al., 2016; Witkin et al., 2017, 2018, 2019, 2020, 2022). This imidazodiazepine, is one of several new GABAkines that have recently been targeted for clinical investigation (Cerne et al., 2021).…”