Deligia, Francesco (2013) Sintesi e caratterizzazione biologica di nuovi 3,6-diazabiciclo[3.1.1]eptani quali potenti e selettivi ligandi per i recettori neuronali nicotinici α4β2 e α7. Doctoral Thesis.
Neuronal nicotinic acetylcholine receptors (nAChRs), activated by the endogenous neurotransmitter acetylcholine and the natural alkaloid nicotine, emerged as important target in drug discovery. Among the plethora of different receptor subtypes the most abundant in the CNS are the α4β2 and the α7 receptors. Since the different nAChRs posses distinctive biophysical, pharmacological and physiological properties, the selective modulation of each subtype represents an intriguing challenge for the development of new drugs for the treatment of different disorders of CNS. In this work we reported optimized methods for the syntheses of novel 3,6-diazabicyclo[3.1.1]heptaneheteroaryl derivates in which the heteroaromatic rings have been modulated by different functionalizations. The changes were made mainly on the pyridine ring in order to investigate the effect of different substitutions on α4β2 and α7 nAChR affinity and selectivity. By preliminary binding studies, the new synthesized compounds showed high affinity for nAChR subtypes and at the same time some derivatives displayed a noticeable α4β2 selectivity. We have designed and synthesized several ligands series for nAChR with a 3,6-diazabicyclo[3.1.1]heptane core linked with aza- or diaza-rings variously substituted. The study allowed the synthesis of derivatives with high affinity and selectivity for nAChRs highlighting as the position of the substituent is a determinant factor for the selectivity on α4β2 receptor subtypes.
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