nAChRs (nicotinic acetylcholine receptors) are neuron receptor proteins that signal for muscular contraction upon a chemical stimulus. In mammals, analysis of cDNA proved existence of 17 homologues of nAChR’s subunits divided into five subtypes: α1-10, β1-4, γ, δ, ɛ. However, subtype α8 is an avian isoform and not exists in mammals. In addition, they are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the presynaptic and postsynaptic sides of the neuromuscular junction. Interestingly, nAChR gets its name from the natural agonist nicotine, a secondary metabolite from a common tobacco plant (Nicotiana tabacum, Solanaceae).
α7 nAChR is an important part of the cholinergic nervous system in the brain. Moreover, it is associated with a cholinergic anti-inflammatory pathway in the termination of the parasympathetic nervous system. Agonists of α7 nAChR are suitable for the treatment of multiple cognitive dysfunctions such as Alzheimer’s disease or schizophrenia. Besides, the agonistic-acting compounds can ameliorate inflammation or even sepsis.
VQW-765 (AQW-051) is a potent, selective and orally active α7-nAChR agonist.
VQW-765 shows a binding efficacy with a pKD value of 7.56 to recombinantly expressed human α7-nACh receptor. It also shows a potent agonist activity to calcium transients that were detected after stimulation of human α7-nACh receptors recombinantly expressed in GH3-ha7-22 cells with a pEC50 value of 7.41.
In vivo, AQW051 demonstrated good oral bioavailability and rapid penetration into the rodent brain. What’s more, VQW-765 increases the cognitive effect and learning/memory performance in the object recognition and social recognition test in mice. Furthermore, VQW-765 shows an anxiolytic-like effect by increasing the social exploration time in rats with a duration of at least 6 h.
All in all, VQW-765, a potent, selective, and orally active α7-nAChR agonist, shows an anxiolytic-like effect in vivo.