title: Preclinical and clinical pharmacology of the GABAA receptor alpha5 subtype-selective inverse agonist alpha5IA.
abstract: alpha5IA is a triazolophthalazine that selectively attenuates the effects of GABA at GABA(A) receptors containing an alpha5 subunit. It enhances long-term potentiation in an in vitro model of mouse hippocampal synaptic plasticity, gives good in vivo receptor occupancy and improves cognitive performance in normal rats as measured using the delayed-matching-to-place version of the Morris water maze yet, importantly, it is without anxiogenic or proconvulsant liabilities. The hydroxymethyl isoxazole metabolite, which occurs both in vitro and in vivo, has a very low aqueous solubility (0.6microg/mL) that resulted in renal toxicity (crystal formation) at very high doses in preclinical safety and toxicity studies. Although this precluded it from being dosed to humans over prolonged periods of time, alpha5IA is, nevertheless, well tolerated in young and elderly subjects up to a dose of 6mg in multiple-dose studies and gives a plasma EC(50) for alpha5IA occupancy measured using [(11)C]flumazenil PET of 10ng/mL. The compound was evaluated in experimental studies and although in elderly subjects alpha5IA does not improve performance in a paired-associate learning task (a 4-mg dose actually impairs performance), it is able to reverse the ethanol-induced impairment in performance in healthy young normal volunteers. These data demonstrate that in man an alpha5-selective inverse agonist may be effective at increasing performance under certain conditions. Whether or not such a compound has efficacy in conditions associated with cognitive deficits, such as attention-deficit hyperactivity disorder, Alzheimer's disease or schizophrenia remains to be determined.
authors.affiliation: Dept. of In Vivo Neuroscience, The Neuroscience Research Centre, Merck Sharp & Dohme Research Labs., Terlings Park, Eastwick Road, Harlow, Essex, UK. JAtack1@its.jnj.com
authors.forename: John R
authors.initials: JR
authors.lastname: Atack
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003071:Cognition / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D054314:Drug Inverse Agonism; D018755:GABA Agonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D058785:GABA-A Receptor Agonists; D006801:Humans; D017774:Long-Term Potentiation / Q000187:drug effects; D008253:Macaca mulatta; D051379:Mice; D010793:Phthalazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; C527986:GABRA5 protein, human; C496250:Gabra5 protein, mouse; C511535:Gabra5 protein, rat; D010793:Phthalazines; D011963:Receptors, GABA-A