Design, synthesis and biological evaluation of novel heterocyclic derivatives targeting the neuronal nicotinic receptor subtypes

()-Cytisine, a natural alkaloid extracted from plants such as Laburnum Anagyroides, behaves mainly as a partial agonist at alpha4beta2 nicotinic acetylcholine receptor subtypes. Moreover, ()-norferruginine, the unnatural nor-analogue of (+)-ferruginine extracted from Darlingia ferruginea, is also more affine for alpha4beta2 neuronal nAChRs. My experimental activity was devoted to the synthesis of a group of derivatives structurally related to Cytisine and Norferruginine. The key step in the preparation of racemates was the 1,3-dipolar cycloaddition of bromonitrile oxide to suitable dipolarophiles, in turn obtained by modifying known reaction sequences. A further investigation of the SAR of cytisine was based on a collaboration with Prof. Gallagher’s research group (University of Bristol, UK). The Gallagher synthesis of cytisine and its analogues involves as a key step a 1,6 addition reaction of a lithium enolate on a pyridone ring. All the compounds have been prepared through palladium catalyzed reactions on the related 4-bromo intermediate (Buchwald-Hartwig, and carbonylation reactions). Another series of compounds has been synthesised taking into account the encouraging results reached by our research group. Based on the structure of ICH3, a selective partial agonist for the alpha7 subtype, I focussed on the evaluation of the relevance of the quinuclidine ring to the biological activity. Applying a molecular simplification strategy, the novel spirocyclic derivatives were prepared via a 1,3-dipolar cycloaddition of nitrile oxides to the suitable olefins. All the compounds were tested for their binding affinity at alpha4beta2 and alpha7 nAChR subtypes.