INVESTIGADORES
MURRAY Ana paula
artículos
Título:
NEW SYNTHETIC CAFFEINE ANALOGS AS MODULATORS OF THE CHOLINERGIC SYSTEM
Autor/es:
FABIANI, CAMILA; BISCUSSI, BRUNELLA; MUNAFO, JUAN PABLO; MURRAY, ANA PAULA; CORRADI, JEREMIAS; ANTOLLINI, SILVIA SUSANA
Revista:
MOLECULAR PHARMACOLOGY
Editorial:
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
Referencias:
Año: 2022 vol. 101 p. 154 - 167
ISSN:
0026-895X
Resumen:
Alzheimer┬┤s disease (AD) is a multifactorial neurodegenerative disorder. Since cholinergic deficit is a major factor in this disease, two molecular targets for its treatment are the acetylcholinesterase (AChE) and the nicotinic acetylcholine receptors (nAChRs). Given that caffeine is a natural compound that behaves as an AChE inhibitor and as a partial agonist of nAChRs, the aim of this work was to synthetize more potent bifunctional caffeine analogs that modulate these two molecular targets. To this end, a theophylline structure was connected to a pyrrolidine structure through a methylene chain of different lengths (3 to 7 carbon atoms) to give compounds 7-11. All caffeine derivatives inhibited the AChE, of which compound 11 showed the strongest effect. Electrophysiological studies showed that all compounds behave as agonists of the muscle and the neuronal α7 nAChR with greater potency than caffeine. To explore if the different analogs could affect the nAChR conformational state, the nAChR conformational sensitive probe crystal violet (CrV) was used. Compounds 9 and 10 conduced the nAChR to a different conformational state comparable with a control nAChR desensitized state. Finally, molecular docking experiments showed that all derivatives interacted with both the catalytic and anionic sites of AChE and with the orthosteric binding site of the nAChR. Thus, the new synthetized compounds can inhibit the AChE and activate muscle and α7 nAChRs with greater potency than caffeine, which suggests that they could be useful leaders for the development of new therapies for the treatment of different neurological diseases.