Synthesis and a4b2 nicotinic affinity of the stereoisomers of 2-(1-methyl-2-pyrrolidinyl)-1,4-benzodioxane and of its nor-methyl derivative

Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels, composed of five subunits forming a pore. The variety of receptor subtypes is mainly due to the diversity of a and b subunits encoded by at least 12 different genes (a2-10, b2-b4). These receptors play an important role in the neurotransmission in the CNS and their dysfunction has been related to a number of severe brain pathologies, including Parkinson’s and Alzheimer’s diseases, schizophrenia, anxiety and some form of epilepsy. As a result novel ligands for neuronal nAchRs, in particular for the two major a4b2 and a7 brain subtypes, may have a great potential as pharmaceutical aiming at several neurological 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 p-electron rich group (HBA/p), which is a 3-pyridinil in nicotine, and/or by conformational flexibility.Recently, we have reported the synthesis and the binding affinity, for a4b2 and a7 nicotinic subtypes, of the RS and SR enantiomers of 1,4-benzodioxane bearing a 1-methyl-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/p. Prompted by the finding that one of the two benzodioxane stereoisomers binds at a4b2 nicotinic receptor with submicromolar affinity, we designed a new synthesis, which allowed all the four stereoisomers of 1 to be obtained from (R)- and (S)-proline. Furthermore, the corresponding nor-methyl derivatives (2) were prepared.