Search

Background and Purpose: Positive allosteric modulators of the α7 nicotinic acetylcholine (nACh) receptor (α7-PAMs) possess promnesic and procognitive properties and have potential in the treatment of cognitive and psychiatric disorders including Alzheimer's disease and schizophrenia. Behavioural studies in rodents have indicated that α7-PAMs can also produce antinociceptive and anxiolytic effects that may be associated with positive modulation of the GABA A receptor. The overall goal of this study was to investigate the modulatory actions of selected α7-PAMs on the GABA A receptor., Experimental Approach: We employed a combination of cell fluorescence imaging, electrophysiology, functional competition and site-directed mutagenesis to investigate the functional and structural mechanisms of modulation of the GABA A receptor by three representative α7-PAMs., Key Results: We show that the α7-PAMs at micromolar concentrations enhance the apparent affinity of the GABA A receptor for the transmitter and potentiate current responses from the receptor. The compounds were equi-effective at binary αβ and ternary αβγ GABA A receptors. Functional competition and site-directed mutagenesis indicate that the α7-PAMs bind to the classic anaesthetic binding sites in the transmembrane region in the intersubunit interfaces, which results in stabilization of the active state of the receptor., Conclusion and Implications: We conclude that the tested α7-PAMs are micromolar-affinity, intermediate- to low-efficacy allosteric potentiators of the mammalian αβγ GABA A receptor. Given the similarities in the in vitro sensitivities of the α7 nACh and α1β2γ2L GABA A receptors to α7-PAMs, we propose that doses used to produce nACh receptor-mediated behavioural effects in vivo are likely to modulate GABA A receptor function., (© 2022 British Pharmacological Society.)

Background and Purpose: α7 nicotinic acetylcholine receptors (α7 nAChRs) may represent useful targets for cognitive improvement. The aim of this study is to compare the pro-cognitive activity of selective α7-nAChR ligands, including the partial agonists, DMXBA and A-582941, as well as the positive allosteric modulator, 3-furan-2-yl-N-p-tolyl-acrylamide (PAM-2)., Experimental Approach: The attentional set-shifting task (ASST) and the novel object recognition task (NORT) in rats, were used to evaluate the pro-cognitive activity of each ligand [i.e., PAM-2 (0.5, 1.0, and 2.0 mg·kg(-1) ), DMXBA and A-582941 (0.3 and 1.0 mg·kg(-1) )], in the absence and presence of methyllycaconitine (MLA), a selective competitive antagonist. To determine potential drug interactions, an inactive dose of PAM-2 (0.5 mg·kg(-1) ) was co-injected with inactive doses of either agonist - DMXBA: 0.1 (NORT); 0.3 mg·kg(-1) (ASST) or A-582941: 0.1 mg·kg(-1) ., Key Results: PAM-2, DMXBA, and A-582941 improved cognition in a MLA-dependent manner, indicating that the observed activities are mediated by α7 nAChRs. Interestingly, the co-injection of inactive doses of PAM-2 and DMXBA or A-582941 also improved cognition, suggesting drug interactions. Moreover, PAM-2 reversed the scopolamine-induced NORT deficit. The electrophysiological results also support the view that PAM-2 potentiates the α7 nAChR currents elicited by a fixed concentration (3 μM) of DMXBA with apparent EC50 = 34 ± 3 μM and Emax = 225 ± 5 %., Conclusions and Implications: Our results support the view that α7 nAChRs are involved in cognition processes and that PAM-2 is a novel promising candidate for the treatment of cognitive disorders., (© 2015 The British Pharmacological Society.)