New analogues of epiboxidine incorporating the 4,5-dihydroisoxazole nucleus: synthesis, binding affinity at neuronal nicotinic acetylcholine receptors, and molecular modeling investigations
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New analogues of epiboxidine incorporating the 4,5-dihydroisoxazole nucleus : synthesis, binding affinity at neuronal nicotinic acetylcholine receptors, and molecular modeling investigations. / Dallanoce, Clelia; Magrone, Pietro; Bazza, Paola; Grazioso, Giovanni; Rizzi, Luca; Riganti, Loredana; Gotti, Cecilia; Clementi, Francesco; Frydenvang, Karla Andrea; De Amici, Marco.
I: Chemistry & Biodiversity, Bind 6, Nr. 2, 2009, s. 244-259.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - New analogues of epiboxidine incorporating the 4,5-dihydroisoxazole nucleus
T2 - synthesis, binding affinity at neuronal nicotinic acetylcholine receptors, and molecular modeling investigations
AU - Dallanoce, Clelia
AU - Magrone, Pietro
AU - Bazza, Paola
AU - Grazioso, Giovanni
AU - Rizzi, Luca
AU - Riganti, Loredana
AU - Gotti, Cecilia
AU - Clementi, Francesco
AU - Frydenvang, Karla Andrea
AU - De Amici, Marco
PY - 2009
Y1 - 2009
N2 - A group of novel 4,5-dihydro-3-methylisoxazolyl derivatives, structurally related to epiboxidine (=(1R,4S,6S)-6-(3-methylisoxazol-5-yl)-7-azabicyclo[2.2.1]heptane), was prepared via 1,3-dipolar cycloaddition 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 (alpha4beta2) and homomeric (alpha7) acetylcholine receptors. Notably, diastereoisomers 1a and 1b were characterized by a massive drop of the affinity at the alpha4beta2 subtypes (K(i) values spanning the range 4.3-126 microM), when compared with that of epiboxidine (K(i)=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 alpha4beta2 receptors. A comparable lack of affinity/selectivity for the two nAChR 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.
AB - A group of novel 4,5-dihydro-3-methylisoxazolyl derivatives, structurally related to epiboxidine (=(1R,4S,6S)-6-(3-methylisoxazol-5-yl)-7-azabicyclo[2.2.1]heptane), was prepared via 1,3-dipolar cycloaddition 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 (alpha4beta2) and homomeric (alpha7) acetylcholine receptors. Notably, diastereoisomers 1a and 1b were characterized by a massive drop of the affinity at the alpha4beta2 subtypes (K(i) values spanning the range 4.3-126 microM), when compared with that of epiboxidine (K(i)=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 alpha4beta2 receptors. A comparable lack of affinity/selectivity for the two nAChR 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.
KW - Former Faculty of Pharmaceutical Sciences
U2 - 10.1002/cbdv.200800077
DO - 10.1002/cbdv.200800077
M3 - Journal article
C2 - 19235154
VL - 6
SP - 244
EP - 259
JO - Chemistry and Biodiversity
JF - Chemistry and Biodiversity
SN - 1612-1872
IS - 2
ER -
ID: 11172887