New analogues of epiboxidine incorporating the 4,5-dihydroisoxazole nucleus: synthesis, binding affinity at neuronal nicotinic acetylcholine receptors, and molecular modeling investigations.
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.
Dallanoce
Clelia
C
Istituto di Chimica Farmaceutica e Tossicologica 'Pietro Pratesi', Università degli Studi di Milano, Via Mangiagalli 25, I-20133 Milano. clelia.dallanoce@unimi.it
Magrone
Pietro
P
Bazza
Paola
P
Grazioso
Giovanni
G
Rizzi
Luca
L
Riganti
Loredana
L
Gotti
Cecilia
C
Clementi
Francesco
F
Frydenvang
Karla
K
De Amici
Marco
M
D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry*; D007700:Kinetics; D008958:Models, Molecular; D011485:Protein Binding; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013329:Structure-Activity Relationship
D007555:Isoxazoles; D011978:Receptors, Nicotinic; C106388:epiboxidine