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 42 and 7 subtype receptors. The moderate and subtype-selective 42 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 42 binding site. The 7-hydroxy derivative was proved to be a potent partial agonist at the 42 and 62 receptors. Other 7-substituted pyrrolidinyl-benzodioxanes are under biological evaluation as well as the pyrrolidinyl-pyridodioxane stereoisomers. High 42 affinity was found for the SS stereoisomer of the opened pyrrolidinyl-pyridodioxane analogue, the pyridiyl ether of 1-(2-N-methylpyrrolidinyl)ethanol.