PWZ-029, a compound with moderate inverse agonist functional selectivity at GABAA receptors containing α5 subunits, improves passive, but not active, avoidance learning in rats

Abstract

Benzodiazepine (BZ) site ligands affect vigilance, anxiety, memory processes, muscle tone and epileptogenic propensity through modulation of neurotransmission at GABA A receptors containing α 1 , α 2 , α 3 or α 5 subunits, and may have numerous experimental and clinical applications. The ability of nonselective BZ site inverse agonists to enhance cognition, documented in animal models and human studies, is clinically not feasible due to potentially unacceptable psychomotor effects. Most investigations to date have proposed the α 1 and/or α 5 subunit-containing GABA A receptors as comprising the memory-modulating population of these receptors. The novel ligand PWZ-029, which we synthesised and characterized electrophysiologically, possesses in vitro binding selectivity and moderate inverse agonist functional selectivity at α 5 -containing GABA A receptors. This ligand has also been examined in rats in the passive and active avoidance, spontaneous locomotor activity, elevated plus maze and grip strength tests, primarily predictive of the effects on the memory acquisition, basal locomotor activity, anxiety level and muscle tone, respectively. The improvement of task learning was detected at the dose of 5 mg/kg in the passive, but not active avoidance test. The inverse agonist PWZ-029 had no effect on anxiety or muscle tone, whereas at higher doses (10 and 20 mg/kg) it decreased locomotor activity. This effect was antagonized by flumazenil and also by the lower (but not the higher) dose of an agonist (SH-053-R-CH3-2'F) selective for GABA A receptors containing the α 5 subunit. The hypolocomotor effect of PWZ-029 was not antagonized by the

In Vitro and in Vivo Properties of 3-tert-Butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)-pyrazolo[1,5-d]-[1,2,4]triazine (MRK-016), a GABAA Receptor α5 Subtype-Selective Inverse Agonist

“…This, along with the interindividual variability in pharmacokinetics that was possibly related to variations in aldehyde oxidase activity, resulted in the termination of the development of this compound. Moreover, although an ␣5-selective inverse agonist has been shown to enhance a pharmacologically (ethanol)-induced cognitive deficit (Nutt et al, 2007), the hypothesis that such a compound might improve performance in a clinically impaired population (e.g., Alzheimer's disease or schizophrenia) remains to be evaluated, although the novel pharmacological properties of compounds such as MRK-016, ␣5IA , PWZ-029 (Savić et al, 2008), and RO4938581 (Ballard et al, 2009) should encourage further studies in this area.…”

Selective targeting of the α5-subunit of GABAA receptors relaxes airway smooth muscle and inhibits cellular calcium handling

“…GABA A receptor ligands active in the central nervous system (CNS) can have many effects including anxiolytic, sedative, hypnotic, amnesic, anticonvulsant, and muscle relaxant effects. This motivated a search for benzodiazepine (BDZ) ligands that discriminate among the ␣-subunits of GABA A receptors (41,42).A novel approach to achieve this goal was developed by Cook and coworkers in the 1980s (1, 25) that employed a pharmacophore/receptor model based on the binding affinity of rigid ligands to BDZ/GABA A receptor sites (8). From this series of receptor models for ␣ 1-6 ␤3␥2 subtypes a robust pharmacophore for ␣5-subtype selective ligands emerged resulting in the synthesis of a novel ␣5␤3␥2 partial agonist modulator:…”

“…GABA A receptor ligands active in the central nervous system (CNS) can have many effects including anxiolytic, sedative, hypnotic, amnesic, anticonvulsant, and muscle relaxant effects. This motivated a search for benzodiazepine (BDZ) ligands that discriminate among the ␣-subunits of GABA A receptors (41,42).…”

Selective Modulators of α₅-Containing GABA_A Receptors and their Therapeutic Significance

“…PWZ-029 is unusual in that it inhibits α 5 GABA A Rs at nanomolar concentrations but potentiates other GABA A R isoforms at much lower potencies [54,55]. In terms of memory-enhancing properties, orally administered PWZ-029 successfully improved the task learning of rats in a hippocampal-dependent passive avoidance test without producing anxiety or convulsions, although hypo-locomotion was observed at higher doses [55].…”

“…PWZ-029 is unusual in that it inhibits α 5 GABA A Rs at nanomolar concentrations but potentiates other GABA A R isoforms at much lower potencies [54,55]. In terms of memory-enhancing properties, orally administered PWZ-029 successfully improved the task learning of rats in a hippocampal-dependent passive avoidance test without producing anxiety or convulsions, although hypo-locomotion was observed at higher doses [55]. In a Pavlovian fear conditioning study, PWZ-029 notably reversed the scopolamine-induced impairment of contextual memory [54], in addition to improving the performance in novel object recognition test [56].…”