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.

In: Chemistry & Biodiversity, Vol. 6, No. 2, 2009, p. 244-259.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Dallanoce, C, Magrone, P, Bazza, P, Grazioso, G, Rizzi, L, Riganti, L, Gotti, C, Clementi, F, Frydenvang, KA & De Amici, M 2009, 'New analogues of epiboxidine incorporating the 4,5-dihydroisoxazole nucleus: synthesis, binding affinity at neuronal nicotinic acetylcholine receptors, and molecular modeling investigations', Chemistry & Biodiversity, vol. 6, no. 2, pp. 244-259. https://doi.org/10.1002/cbdv.200800077

APA

Dallanoce, C., Magrone, P., Bazza, P., Grazioso, G., Rizzi, L., Riganti, L., Gotti, C., Clementi, F., Frydenvang, K. A., & De Amici, M. (2009). New analogues of epiboxidine incorporating the 4,5-dihydroisoxazole nucleus: synthesis, binding affinity at neuronal nicotinic acetylcholine receptors, and molecular modeling investigations. Chemistry & Biodiversity, 6(2), 244-259. https://doi.org/10.1002/cbdv.200800077

Vancouver

Dallanoce C, Magrone P, Bazza P, Grazioso G, Rizzi L, Riganti L et al. New analogues of epiboxidine incorporating the 4,5-dihydroisoxazole nucleus: synthesis, binding affinity at neuronal nicotinic acetylcholine receptors, and molecular modeling investigations. Chemistry & Biodiversity. 2009;6(2):244-259. https://doi.org/10.1002/cbdv.200800077

Author

Dallanoce, Clelia ; Magrone, Pietro ; Bazza, Paola ; Grazioso, Giovanni ; Rizzi, Luca ; Riganti, Loredana ; Gotti, Cecilia ; Clementi, Francesco ; Frydenvang, Karla Andrea ; De Amici, Marco. / New analogues of epiboxidine incorporating the 4,5-dihydroisoxazole nucleus : synthesis, binding affinity at neuronal nicotinic acetylcholine receptors, and molecular modeling investigations. In: Chemistry & Biodiversity. 2009 ; Vol. 6, No. 2. pp. 244-259.

Bibtex

@article{f4bdc0700c8a11de8478000ea68e967b,
title = "New analogues of epiboxidine incorporating the 4,5-dihydroisoxazole nucleus: synthesis, binding affinity at neuronal nicotinic acetylcholine receptors, and molecular modeling investigations",
abstract = "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.",
keywords = "Former Faculty of Pharmaceutical Sciences",
author = "Clelia Dallanoce and Pietro Magrone and Paola Bazza and Giovanni Grazioso and Luca Rizzi and Loredana Riganti and Cecilia Gotti and Francesco Clementi and Frydenvang, {Karla Andrea} and {De Amici}, Marco",
year = "2009",
doi = "10.1002/cbdv.200800077",
language = "English",
volume = "6",
pages = "244--259",
journal = "Chemistry & Biodiversity",
issn = "1612-1872",
publisher = "Wiley - V C H Verlag GmbH & Co. KGaA",
number = "2",

}

RIS

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 & Biodiversity

JF - Chemistry & Biodiversity

SN - 1612-1872

IS - 2

ER -

ID: 11172887