INVESTIGADORES
MURRAY Ana paula
congresos y reuniones científicas
Título:
Synthesis and functional evaluation of new analogs of caffeine as modulators of the cholinergic system
Autor/es:
FABIANI, CAMILA; BISCUSSI, BRUNELLA; MUNAFÓ, JUAN PABLO; CORRADI, JEREMÍAS; ANA PAULA MURRAY; ANTOLLINI, SILVIA SUSANA
Lugar:
Reunion Virtual
Reunión:
Congreso; XXXV Annual Meeting, Sociedad Argentina de Neurociencias; 2020
Institución organizadora:
Sociedad Argentina de Neurociencias
Resumen:
Cholinergic deficit is regarded as an important factor in Alzheimer?s disease. Two molecular targets for its treatment are the acetylcholinesterase (AChE) and the nicotinic receptor (nAChR). Previously, we demonstrated that caffeine acts on nAChRs as a partial agonist and it is known that it also inhibits AChE. Here, we synthetized more potent bifunctional caffeine analogs. A theophylline structure was connected with a pyrrolidine structure through a methylene chain of different lengths (3 to 7 carbon atoms) to form the compounds 7-11. We found that all the derivatives inhibited the AChE, having compound 11 the strongest effect. To explore if the analogs influence the nAChR conformational state, the nAChR conformational-sensitive probe crystal violet (CrV) and nAChR-rich membranes from 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 underlying these conformational changes, we recorded single-channel events from the muscle nAChR. We observed that all the compounds activated muscle nAChR at low concentrations and the activation was as isolated openings even at the highest Cn concentrations. Thus, our results demonstrate that the new compounds behave as dual modulators by acting as AChE inhibitors and as wick nAChR agonists. To gain insights about the molecular interaction of these compounds with both receptors we performed in-silico studies. Our results bring new information about the mechanism of modulation of pharmacologic targets for the design of new therapies for the intervention in neurological diseases.