New functional caffeine analogs as possible multitarget potentiators of the cholinergic system

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

Ciudad Autónoma de Buenos Aires

Congreso; XLIX Reunión Anual de la Sociedad Argentina de Biofísica; 2021

Sociedad Argentina de Biofísica

Since cholinergic deficit is characteristic of Alzheimer's disease, two possible moleculartargets for its treatment are the acetylcholinesterase (AChE) and the nicotinicacetylcholine receptors (nAChRs). In previous studies of our group, we found that caffeinebehaves as an agonist of the nAChRs and confirmed that it inhibits the AChE. Wesubsequently synthetized hybrid caffeine analogs by connecting a theophyllinegroupwith a pyrrole group via a carbon linker of different lengths (3 to 7 carbon atoms).All the compounds inhibited the AChE and activated the nAChR with higher potency thancaffeine. Some of them conduct the receptor to a desensitized and agonist-refractingstate, while others make the receptor quickly return to a resting, agonist-responding state.Based on these results, in this work we synthetized three new hybrid analogsof thesynthetic compound with a linker of 5 carbon atoms, which belongs to the desensitizinggroup, maintaining the theophylline structure but changing the pyrrole group bypiperidine, 1-methylpiperazine or dimethylamine. All analogs inhibited the AChE withhigher potency than the precursor. Using Crystal violet (CrV) fluorescence probe, an openchannel blocker with higher affinity for the desensitized thanfor the resting state of thenAChR, we observed that the compounds with piperidine and 1-methylpiperazinecausednAChR conformational changes that could be related to a conformational transitioncorresponding toreceptor activation followed bya stabilization in the desensitized state. Incontrast, the compound with the dimethylamine group did not conduct the nAChR to adesensitized state. Our results provide new insights into structure-activity relationship forthis group of functional multi-target drugs giving valuable tools to transform the search ofnew drugs from random screening into a detailed rational drug designof newinterventional therapies in neurological diseases.