NUOVI LIGANDI DEI RECETTORI NICOTINICI NEURONALI: BENZODIOSSANI E PIRIDODIOSSANI 2-PIRROLIDINIL SOSTITUITI

Pyrrolidinyl-benzodioxanes and pyrrolidinyl-pyridodioxanes, rigidified analogues of well known prolinol phenyl ethers and prolinol pyridyl ethers respectively, were synthesized in unichiral form and tested for neuronal nicotinic affinity at \uf0614\uf0622 and \uf0617 subtype receptors. The moderate and subtype-selective \uf0614\uf0622 affinity of the SR stereoisomer of N-methylated 2-(2-pyrrolidinyl)benzodioxane was enhanced from submicromolar to nanomolar by introducing a hydroxyl at the C(7) of benzodioxane nucleus. Docking analysis clearly rationalized the beneficial effect of the substituent, which interacts with specific amino acid residues in the at \uf0614\uf0622 binding site. The 7-hydroxy derivative was proved to be a potent partial agonist at the \uf0614\uf0622 and \uf0616\uf0622 receptors. Other 7-substituted pyrrolidinyl-benzodioxanes are under biological evaluation as well as the pyrrolidinyl-pyridodioxane stereoisomers. High \uf0614\uf0622 affinity was found for the SS stereoisomer of the opened pyrrolidinyl-pyridodioxane analogue, the pyridiyl ether of 1-(2-N-methylpyrrolidinyl)ethanol