A group of novel 4,5-dihydro-3-methylisoxitzolyl derivatives, structurally related to epiboxidine (= (1R,4S,6S)-6-(3-methylisoxazol-5-yl)-7-azzibicyclo[2.2.1]heptane), was prepared via 1,3-dipolar cyclo-addition of acetonitrile oxide to different olefins. Target compounds 1a and 1b, 2a and 2b, 3, 4, and 5 were tested for affinity at neuronal nicotinic heteromeric (alpha 4 beta 2) and homomeric (alpha 7) acetylcholine receptors. Notably, diastereoisomers 1a and 1b were characterized by a massive drop of the affinity at the alpha 4 beta 2 subtypes (K(i) values spanning the range 4.3-126 mu M), when compared with that of epiboxidine (Ki = 0.6 nM). Therefore, the replacement of the 3-methylisoxazole ring of epiboxidine with the 4.5-dihydro-3-methylisoxazole nucleus is detrimental for the affinity at alpha 4 beta 2 receptors. A comparable lack of affinity/selectivity for the two nACh R subtypes under study was evidenced for the remaining epiboxidine-related dihydroisoxazole derivatives 2a and 2b. and 3-5. Diastereoisomers 1a and 1b, and spirocyclic derivative 3 were docked into molecular models of the receptor subtypes under study, and their binding mode was compared with that of reference ligands endowed with high binding affinity.
New analogues of epiboxidine incorporating the 4,5-dihydroisoxazole nucleus: Synthesis, binding affinity at neuronal nicotinic acetylcholine receptors, and molecular modeling investigations / C. Dallanoce, L. Rizzi, P. Magrone, P. Bazza, G. Grazioso, L. Riganti, C. Gotti, F. Clementi, K. Frydenvang, M. De Amici. - In: CHEMISTRY & BIODIVERSITY. - ISSN 1612-1872. - 6:2(2009), pp. 244-259.
|Titolo:||New analogues of epiboxidine incorporating the 4,5-dihydroisoxazole nucleus: Synthesis, binding affinity at neuronal nicotinic acetylcholine receptors, and molecular modeling investigations|
DALLANOCE, CLELIA MARIANGIOLA LUISA (Corresponding)
RIZZI, LUCA (Secondo)
DE AMICI, MARCO (Ultimo)
|Parole Chiave:||epibatidine; agonists; (+/-)-epibatidine; derivatives; selectivity; diversity; products; alcohols; ligands; systems|
|Settore Scientifico Disciplinare:||Settore CHIM/08 - Chimica Farmaceutica|
Settore BIO/14 - Farmacologia
|Data di pubblicazione:||2009|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1002/cbdv.200800077|
|Appare nelle tipologie:||01 - Articolo su periodico|