AC4-ASA, a novel heterobifunctional probe and competitive and allosteric ligand of the muscle nicotinic acetylcholine receptor.

DEL CANTO, SERGIO G., ORMAN BETINA E., STERIN DE BORDA, LEONOR J., BISCOGLIO DE JIMÉNEZ BONINO, MIRTHA.

Córdoba, Argentina

Congreso; SAN 2009; 2009

Sociedad Argentina de Neuroquímica

The probe was developed as a tool for the study of cholinergic receptor binding sites. In order to achieve that, acetylcholine was derivatized at its alkyl end and through a short spacer, with a photoactivatable aryl-azide group susceptible to radioiodination. The synthesis and purification procedures were simple and the probe proved to be stable in the dark. Besides, it was able to interact specifically with muscarinic and muscle nicotinic receptors showing to be an agonist of the former and having (a good??) selectivity for the á/ä binding site of the latter. The ligand presented the capability of modyfing the affininty of (-)-[3H]-nicotine by the muscle-type nicotinic receptor. Competition experiments between AC4-ASA and (-)-[3H]-nicotine revealed that the ligand could perform its modulating activity through, at least, a new allosteric binding site, different from the typical orthosteric binding sites. Future photolabelling experiments will display its location at the receptor. Moreover, we would like to point out the ligand potential use for the study of the structural changes undergone by the nicotinic receptor interfaces during activation.