SYNTHESIS AND BINDING AFFINITY OF NEW HIGHLY SELECTIVE alpha4beta2 NICOTINIC LIGANDS

Nicotinic receptors play an important role in the regulation of neurotransmission in the CNS and their dysfunction has been related to a number of severe brain pathologies. As a result, novel ligands for neuronal nicotinic receptors, in particular for the two major α4β2 and α7 brain subtypes, may have a great potential for the treatment of several neurodegenerative disorders. Nicotine, the prototype of nicotinic agonists, has inspired the design of novel nicotinoids, mainly differing by the nature of the hydrogen bond acceptor and π-electron-rich group (HBA/π), that is 3-pyridinyl in nicotine, and/or by conformational flexibility. Recently, we have reported the synthesis and the binding affinity, for α4β2 and α7 nicotinic subtypes, of all the stereiosomers of 1,4-benzodioxane bearing a 2-pyrrolidinyl substituent at the 2-position (1).1 The designed structure, which can be seen as a rigidified analogue of nicotinic ligands such as prolinol phenyl ethers, is characterized by the presence of two vicinal stereocentres. These are connected by the sole bond, whose rotation is relevant to molecule conformation, and are placed in proximity of the critical cationic head with important consequences on the mutual disposition of N+ and HBA/π. Prompted by the finding that two of the four benzodioxane stereoisomers bind at α4β2 nicotinic receptor with submicromolar affinity, we have focused our research on the modification of its benzene ring, introducing CH3, CH2OH, COCH3, Ph, OH, OMe, O-iPr, Br into the benzodioxane 7-position (compounds 2-9). All these structure are characterized by the presence of two stereocentres, connected by the only bond, whose rotation is relevant to molecule conformation. Rigidity and stereochemical complication in the proximity of functions critically involved in binding site interaction can be very helpful and desirable in view of identifying new templates. Herein, we report the synthesis, the binding affinity for nicotinic receptors subtypes, the docking analysis of all the stereoisomers of compounds 2-9 and discussing the structure-activity relationships.