We report the design, synthesis and pharmacological screening of a group of analogues of anabaseine 2, a naturally occurring unselective nicotinic agonist. The novel nAChR ligands 5-15 were planned following a molecular modeling analysis which suggested the replacement of the pyridine ring of 2 with a 3-substituted benzene ring as a means to gain selectivity for the α3β4 nAChR subtype. Overall, from binding experiments, the synthesized compounds showed high values of α3β4 affinity and α3β4 vs α4β2 selectivity, although they poorly discriminated the homomeric α7 subtype. The three analogues 6, 12 and 13 were also evaluated in electrophysiological assays, and 12 [6-(3-iodophenyl)-2,3,4,5-tetrahydropyridine] emerged as a rather interesting nicotinic ligand. Indeed, in addition to a noteworthy affinity (Ki = 4.7 nM) for the α3β4 subtype and to an excellent α3β4 vs α4β2 subtype selectivity (806-fold), compound 12 selectively activated the α3β4 nAChR (EC50 = 7.4 μM) while eliciting a negligible response at the α7 subtype and no effect at the α4β2 subtype.
Modification of the anabaseine pyridine nucleus allows achieving binding and functional selectivity for the α3β4 nicotinic acetylcholine receptor subtype / C. Matera, M. Quadri, M. Sciaccaluga, D.Y. Pomè, F. Fasoli, M. De Amici, S. Fucile, C. Gotti, C. Dallanoce, G. Grazioso. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 108(2016 Jan), pp. 392-405.
|Titolo:||Modification of the anabaseine pyridine nucleus allows achieving binding and functional selectivity for the α3β4 nicotinic acetylcholine receptor subtype|
MATERA, CARLO (Primo)
QUADRI, MARTA (Secondo)
DALLANOCE, CLELIA MARIANGIOLA LUISA (Corresponding)
GRAZIOSO, GIOVANNI (Ultimo)
|Parole Chiave:||Anabaseine-related derivatives; Binding affinity; Design; Functional activity/selectivity; Molecular modeling; Neuronal nicotinic acetylcholine receptors; α3β4 nicotinic ligands; Drug Discovery3003 Pharmaceutical Science; Organic Chemistry; Pharmacology|
|Settore Scientifico Disciplinare:||Settore CHIM/08 - Chimica Farmaceutica|
|Data di pubblicazione:||gen-2016|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.ejmech.2015.11.045|
|Appare nelle tipologie:||01 - Articolo su periodico|