| Title : New analogues of epiboxidine incorporating the 4,5-dihydroisoxazole nucleus: synthesis, binding affinity at neuronal nicotinic acetylcholine receptors, and molecular modeling investigations - Dallanoce_2009_Chem.Biodivers_6_244 |
| Author(s) : Dallanoce C , Magrone P , Bazza P , Grazioso G , Rizzi L , Riganti L , Gotti C , Clementi F , Frydenvang K , De Amici M |
| Ref : Chem Biodivers , 6 :244 , 2009 |
| 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. |
| ESTHER : Dallanoce_2009_Chem.Biodivers_6_244 |
| PubMedSearch : Dallanoce_2009_Chem.Biodivers_6_244 |
| PubMedID: 19235154 |
Dallanoce C, Magrone P, Bazza P, Grazioso G, Rizzi L, Riganti L, Gotti C, Clementi F, Frydenvang K, 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
Chem Biodivers
6 :244
Dallanoce C, Magrone P, Bazza P, Grazioso G, Rizzi L, Riganti L, Gotti C, Clementi F, Frydenvang K, De Amici M (2009)
Chem Biodivers
6 :244