Synthesis and functional evaluation of new analogs of caffeine as modulators of the cholinergic system

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

Congreso; XXXV Annual Meeting of the Argentinian Society for Neuroscience Research (SAN 2020); 2020

Sociedad Argentina de Investigación en Neurociencias

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 analogs. A theophylline fragment was connected with a pyrrolefragment through homologation from 3 to 7 carbon atoms to form the compounds C3 toC7 (Cn). We found that all Cn inhibited the AChE, having C7 the strongest effect. Toexplore if the analogs influence the nAChR conformational state, crystal violet (CrV) andnAChR-rich membranes from T. californica were used. The analogs produced changes inthe KD values of CrV, being C5 and C6 the most potent. To understand the molecularmechanism underlying these conformational changes, we recorded single-channel eventsfrom muscle nAChR. The compounds activated muscle nAChR at low concentrations andthe activation was as isolated openings even at the highest Cn concentrations. Ourresults demonstrate that the new compounds behave as dual modulators by acting asAChE inhibitors and as nAChR agonists. To gain insight about the molecular interaction ofthese compounds with nAChR we performed in-silico studies. Our results bring newinformation about the mechanism of modulation of pharmacologic targets for the designof new therapies for the intervention in neurological diseases.