New Analogues of Epiboxidine Incorporating the 4,5-Dihydroisoxazole Nucleus: Synthesis, Binding Affinity at Neuronal Nicotinic Acetylcholine Receptors, and Molecular Modeling Investigations
✍ Scribed by Clelia Dallanoce; Pietro Magrone; Paola Bazza; Giovanni Grazioso; Luca Rizzi; Loredana Riganti; Cecilia Gotti; Francesco Clementi; Karla Frydenvang; Marco De Amici
- Publisher
- John Wiley and Sons
- Year
- 2009
- Tongue
- English
- Weight
- 454 KB
- Volume
- 6
- Category
- Article
- ISSN
- 1612-1872
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✦ Synopsis
Abstract
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A group of novel 4,5‐dihydro‐3‐methylisoxazolyl derivatives, structurally related to epiboxidine (=(1__R__,4__S__,6__S__)‐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 (__α__4__β__2) and homomeric (__α__7) acetylcholine receptors. Notably, diastereoisomers 1a and 1b were characterized by a massive drop of the affinity at the __α__4__β__2 subtypes (K~i~ values spanning the range 4.3–126 μM), 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 __α__4__β__2 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.