Functional in vivo correlates of the benzodiazepine agonist-inverse agonist continuum

Diazepam as a Treatment for Metronidazole Toxicosis in Dogs: A Retrospective Study of 21 Cases

“…[38][39][40] Conversely, inhibition of GABA release, such as seen in the neurological adverse effects of enrofloxacin, i ciprofloxacin, j and imipenem, k can lead to hyperexcitability of the central nervous system, resulting in seizures or tremors. 41,42 It may therefore be speculated that interference of the GABA receptor at the postsynaptic membrane also may result in central nervous system hyperexcitability.…”

“…The benzodiazepines have specific binding sites on GABA receptors within the brain, particularly in the cerebellum, cerebral cortex, and limbic system. 41,43 The imidazobenzodiazepine flumazenil is a selective, competitive antagonist (also known as an inverse agonist) of the benzodiazepine receptor. 40,41,[44][45][46][47] Both flumazenil and metronidazole have an imidazole component, and it is possible that metronidazole also may bind specifically to benzodiazepine sites on GABA receptors in the cerebellar and central vestibular systems, resulting in loss of inhibition, similar in effect to flumazenil (Fig 3).…”

“…41,43 The imidazobenzodiazepine flumazenil is a selective, competitive antagonist (also known as an inverse agonist) of the benzodiazepine receptor. 40,41,[44][45][46][47] Both flumazenil and metronidazole have an imidazole component, and it is possible that metronidazole also may bind specifically to benzodiazepine sites on GABA receptors in the cerebellar and central vestibular systems, resulting in loss of inhibition, similar in effect to flumazenil (Fig 3). That the adverse reactions of flumazenil in humans, such as seizures, vertigo, and ataxia, [45][46][47] are similar to the neurological adverse effects of metronidazole in dogs lends additional credence to this proposed mechanism of metronidazole toxicity.…”

GABA agonists and antagonists

“…However, true antagonists at benzodiazepine sites are known, that block each of these previous actions, without themselves eliciting any influence on GABAA-receptor-mediated responses. 22 The present nomenclature for describing bidirectional allosteric modulation at benzodiazepine receptor sites is rather unsatisfactory, possibly misleading.…”

Molecular targets for the rational design of antiepileptic drugs and related neuroprotective agents

“…The possibility of partial agonists existing within this continuum is intriguing, as they may be devoid of typical BZD-mediated side effects such as physical dependence, amnesia, oversedation (anxiolytics), and muscle relaxation. [158][159][160] The pyrido[1,2-a]benzimidazole (PBI) compounds (36, Fig. 11), are potent ligands for the BZD binding site on GABA A receptors, and show strong ability to block the tonic-ANTIEPILEPTIC DRUGS 553 .…”