Novel bicyclic Delta2-isoxazoline and 3-oxo-isoxazolidine derivatives: synthesis and binding affinity at neuronal nicotinic receptor subtypes

Neuronal nicotinic acetylcholine receptors (nAChRs) are involved in various processes such as cognition, learning and memory, cerebral blood flow and metabolism, as well as an array of pathological conditions such as Alzheimer’s and Parkinson’s diseases, mild cognitive impairment (MCI), schizophrenia, epilepsy, Tourette’s syndrome, anxiety, depression, attention-deficit hyperactivity disorder (ADHD), and nicotine addiction. As an extension of our studies focused on new Delta2-isoxazoline derivatives and their affinity/efficacy profiles at alpha4beta2 and alpha7 nAChRs [1, 2], we synthesized the group of derivatives 4-9, which may be related to (-)-Cytisine 1 and (-)-Norferruginine 3. The target chiral compounds, obtained by means of pericyclic reactions, were prepared and tested as racemates. The synthetic details and the results of the pharmacological investigation will be presented and discussed. [1] Dallanoce, C.; Bazza, P.; Grazioso, G.; De Amici, M.; Gotti, C.; Riganti, L.; Clementi, F.; De Micheli, C. Synthesis of Epibatidine-related 2-Ixoxazoline Derivatives and Evaluation of their Binding Affinity at Neuronal Nicotinic Acetylcholine Receptors. Eur. J. Org. Chem. 2006; 3746-3754. [2] De Micheli, C.; De Amici, M.; Dallanoce, C.; Clementi, F.; Gotti, C. Preparation of Azabicyclic Spiro Compounds as Agonists of 7 Nicotinic Acetylcholine Receptors. PCT Int. Appl. WO 2008000469 (2008).