New caffeine analogs as promising multitarget drugs for cholinergic deficiency

MUNAFO, J.P.; BISCUSSI, B.; OBIOL, D.; COSTABEL, M.; BOUZAT, C.; MURRAY, A.P.; ANTOLLINI, S.S.

Congreso; LI Reunión Anual de la Sociedad Argentina de Biofísica; 2023

Sociedad Argentina de Biofísica

Previously, we found that caffeine acts as a partial agonist of both muscle and neuronalnicotinic acetylcholine receptors (nAChR) and confirmed that it also inhibitsacetylcholinesterase (AChE). Cholinergic deficiency is a characteristic feature of severalpathologies, such as myasthenia gravis, certain types of congenital myasthenicsyndromes and Alzheimer's disease whereas AChE and nAChR are the two main moleculartargets for its treatment. Thus, caffeine becomes a promising new multitarget leader forboth molecular targets. In this study, we synthesized novel bifunctional caffeinederivatives. All of them were more potent AChE inhibitors than caffeine. Byelectrophysiological and fluorescence spectroscopy studies, we observed that some ofthem also behaved as partial agonists of muscle nAChR, but not all stabilized the nAChR ina desensitized state. In silico studies were performed to understand the molecularmechanism underlying these results. Taken together, all these results give valuableinformation about the necessary pharmacophoric chemical properties for both nAChR andAChE molecular targets and provide knowledge about the mechanisms of modulation ofthese both pharmacological targets which may have implications for the design of newtherapeutic strategies in neurological disorders.