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

MUNAFÓ, JUAN PABLO; BISCUSSI, BRUNELLA; OBIOL, DIEGO; COSTABEL, MARCELO; BOUZAT, CECILIA; ANA PAULA MURRAY; ANTOLLINI, SILVIA

ACS Chemical Neuroscience

American Chemical Society

Año: 2024 vol. 15 p. 994 - 1009

1948-7193

Cholinergic deficit is a characteristic factor of several pathologies, such as myasthenia gravis, some types of congenital 6 myasthenic syndromes, and Alzheimerś Disease. Two molecular targets for its treatment are acetylcholinesterase (AChE) and 7 nicotinic acetylcholine receptor (nAChR). In previous studies, we found that caffeine behaves as a partial nAChR agonist and 8 confirmed that it inhibits AChE. Here, we present new bifunctional caffeine derivatives consisting of a theophylline ring connected to 9 amino groups by different linkers. All of them were more potent AChE inhibitors than caffeine. Furthermore, although some of them 10 also activated muscle nAChR as partial agonists, not all of them stabilized nAChR in its desensitized conformation. To understand11 the molecular mechanism underlying these results, we performed docking studies on AChE and nAChR. The nAChR agonist 12 behavior of the compounds depends on their accessory group, whereas their ability to stabilize the receptor in a desensitized state 13 depends on the interactions of the linker at the binding site. Our results show that the new compounds can inhibit AChE and14 activate nAChR with greater potency than caffeine and provide further information on the modulation mechanisms of 15 pharmacological targets for the design of novel therapeutic interventions in cholinerg