Screening of positive allosteric modulators for the alpha9-alpha10 nicotinic cholinergic receptor

AGUERO, L; GALLINO, S; DALAMON, V; GOMEZ CASATI, ME; ELGOYHEN, AB

Congreso; Congreso anual de la Sociedad de Neurociencias; 2023

Hearing loss affects 360 million people (5% of the world’s population and 42% of the population over 75 years of age). While half of hearing loss is genetic in origin, the other 50% is due to environmental conditions. Among them, prolonged exposure to loud noise is the main cause of hearing loss. One of the main challenges in the field of hearing is to find a pharmacotherapeutic strategy to prevent the damage produced by noisy environments, when these cannot be avoided. Recent studies have postulated the ?9?10 nicotinic cholinergic receptor present in the sensory hair cells of the cochlea as a therapeutic target for the development of drugs that increase the activity of the olivocochlear efferent system, in order to prevent acoustic trauma. The aim of this work is to test possible positive allosteric modulators (PAMs) of ?9?10 and their potential to prevent hearing loss due to the exposure to loud noise. To this end, we tested several candidates for PAMs or agonists of certain receptors that are closely or distantly related to ?9?10 such as ?7, ?4?2 or ?4?4 and serotonin receptors in recombinant ?9?10 receptors expressed in Xenopus laevis oocytes. Up to this point, Chlorophenyl biguanide, a selective serotonin receptor agonist, has been evaluated; also Ivermectin and TQS, PAMs of ?7 nAChRs; NS-9283, an ?4?2 nAChR PAM; and LY–2087101 PAM of ?7, ?4?2 and ?4?4 nAChRs which did not positively modulate the ?9?10 receptor.