Modulation of the cholinergic system by synthetic derivatives of caffeine

FABIANI, CAMILA; BISCUSSI, BRUNELLA; MUNAFÓ, JUAN PABLO; CORRADI, JEREMÍAS; ANA PAULA MURRAY; ANTOLLINI, SILVIA SUSANA

Reunion Virtual

Congreso; Primeras jornadas virtuales de la Sociedad Argentina de Biofísica; 2020

Sociedad Argentina de Biofísica

Cholinergic deficit is regarded as an important factor in Alzheimer’s disease. Twomolecular targets for its treatment are the acetylcholinesterase (AChE) and the nicotinicreceptor (nAChR). We previously demonstrated that caffeine acts on nAChRs as a weakagonist and it is known that it inhibits AChE. Here, we synthetized more potentbifunctional caffeine derivatives or analogs. A theophylline fragment was connected witha pyrrole fragment through homologation from 3 to 7 carbon atoms to form thecompounds C3 to C7 (C n). We found that all Cn inhibited the AChE, having C 7 thestrongest effect. To explore if the analogs influence the nAChR conformational state, thenAChR conformational-sensitive probe crystal violet (CrV) and nAChR-rich membranesfrom T. californica were used. The analogs produced changes in the KD values of CrV,being C5 and C6 the most potent. To understand the molecular mechanism underlyingthese conformational changes, we recorded single-channel events from the musclenAChR. We observed that all the compounds activated muscle nAChR at lowconcentrations and the activation was as isolated openings even at the highest Cnconcentrations. Thus, our results demonstrate that the new compounds behave as dualmodulators by acting as AChE inhibitors and as wick nAChR agonists. To gain insightsabout the molecular interaction of these compounds with both receptors we performedin-silico studies. Our results bring new information about the mechanism of modulationof pharmacologic targets for the design of new therapies for the intervention inneurological diseases.