New analogues of epiboxidine incorporating the 4,5-dihydroisoxazole nucleus: synthesis, binding affinity at neuronal nicotinic acetylcholine receptors, and molecular modeling investigations

Clelia Dallanoce; Pietro Magrone; Paola Bazza; Giovanni Grazioso; Luca Rizzi; Loredana Riganti; Cecilia Gotti; Francesco Clementi; Karla Andrea Frydenvang; Marco De Amici

doi:10.1002/cbdv.200800077

New analogues of epiboxidine incorporating the 4,5-dihydroisoxazole nucleus: synthesis, binding affinity at neuronal nicotinic acetylcholine receptors, and molecular modeling investigations

Clelia Dallanoce, Pietro Magrone, Paola Bazza, Giovanni Grazioso, Luca Rizzi, Loredana Riganti, Cecilia Gotti, Francesco Clementi, Karla Andrea Frydenvang, Marco De Amici

13 Citations (Scopus)

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.

Original language	English
Journal	Chemistry & Biodiversity
Volume	6
Issue number	2
Pages (from-to)	244-259
ISSN	1612-1872
DOIs	https://doi.org/10.1002/cbdv.200800077
Publication status	Published - 2009

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Former Faculty of Pharmaceutical Sciences

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10.1002/cbdv.200800077

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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

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 et al.

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

Research output: Contribution to journal › Journal article › Research › peer-review

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

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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.",

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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",

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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

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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

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DO - 10.1002/cbdv.200800077

M3 - Journal article

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SN - 1612-1872

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EP - 259

JO - Chemistry and Biodiversity

JF - Chemistry and Biodiversity

IS - 2

ER -

New analogues of epiboxidine incorporating the 4,5-dihydroisoxazole nucleus: synthesis, binding affinity at neuronal nicotinic acetylcholine receptors, and molecular modeling investigations

Abstract

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