New multitarget molecules derived from caffeine as modulators of the cholinergic system

MUNAFÓ, JUAN PABLO; BISCUSSI, BRUNELLA; FABIANI, CAMILA; OBIOL, D; COSTABEL, MARCELO; BOUZAT, CECILIA; ANA PAULA MURRAY; ANTOLLINI, SILVIA SUSANA

Rosario

Congreso; L Reunión Anual de la Sociedad Argentina de Biofísica; 2022

Sociedad Argentina de Biofísica

Cholinergic deficit is a characteristic factor of Alzheimer´s disease. Two possible moleculartargets for its treatment are the acetylcholinesterase (AChE) and the nicotinicacetylcholine receptors (nAChR). In previous studies, we found that caffeine behaves as apartial nAChR agonist and confirmed that it inhibits AChE. Based on these findings, in thiswork we obtained 8 more potent bifunctional derivatives for these molecular targets. Theyconsisted of a theophylline ring connected to several chemical groups (pyrrole, piperidine,methylpiperazine, or diethylamine) by different linkers (linear chains of 5 and 7 carbonatoms (C5 and C7) or C3-NH-C2 and C5-NH-C2 chains). All of them were more potentAChE inhibitors than caffeine. Electrophysiological studies by single-channelmeasurements in adult muscle nAChR transiently expressed in BOSC23 cells showed thatall compounds, except C5 and C7 diethylamine, activated the nAChR, being C7-piperidinethe most active. To understand the molecular mechanism underlying receptor activation,we further explored whether these analogs influence the conformational state of nAChRusing nAChR-rich membranes of T. californica and crystal violet (CrV), a sensitive probe forthe conformation of nAChRs. We observed that only C5-piperidine stabilized the nAChR ina desensitized state. Finally, we carried out in silico studies on AChE and nAChR (with itsloop C partially closed) to obtain information on the molecular interactions among thesecompounds and both molecular targets. Altogether, our results show that the newsynthetized compounds can inhibit the AChE and activate the nAChR with greaterpotency than caffeine and provide further information on the modulation mechanisms ofpharmacological targets for the design of novel therapeutic interventions in neurologicaldiseases.