Design, synthesis and pharmacology of novel ligands targeting neuronal nicotinic acetylcholine receptor subtypes

Neuronal nicotinic acetylcholine receptors (nAChRs) make up a family of pentameric ligand-gated ion channels which are formed by combinations of alpha and beta subunits or exist as homopentamers, in the cases of α-7, α-8, and α-9 receptors, which are inhibited by α-bungarotoxin. To date, nine α (α-2-α-10) and three β(β2-β4) isoforms have been characterized, though only a relatively small subset of combinations generates functionally and physiologically relevant channels. Nicotinic receptors are widely distributed in the brain, where they primarily modulate the release of other neurotransmitters and, to a lesser extent, mediate synaptic transmission. Neuronal 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. The heteromeric α4β2 and the homomeric α7 nAChR subtypes represent the most relevant biological targets in view of potential therapeutic applications for the above cited pathologies. In this study, the group of novel stereoisomeric Δ2-isoxazolines 1a-1f and 2a-f, structurally related to the α4β2 selective nicotinic agonist ABT-418, has been prepared and tested at neuronal α4β2 and α7 nAChR subtypes. Moreover, (-)-Cytisine 3, a natural selective α4β2 ligand, was taken as model compound to synthesize the group of 4-substituted derivatives 4-8.The two series of derivates were synthesized by taking advantage of a 1,3-dipolar or a 1,6-intramolecular cycloaddition processes.On the other hand, as an extension of a previous research project, we prepared a group of novel derivatives characterized by a spirocylic junction between the quinuclidine ring and the Δ2-isoxazoline (8a-g and 9a-g) or the isoxazolidin-3-one (10a-b) moieties. Some of the compounds under study behaved as potent and selective α7 nAChR agonists/partial agonists and were further investigated in in vitro and in vivo tests.