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 42 and 7 subtype receptors. The moderate and subtype-selective 42 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 42 binding site. The 7-hydroxy derivative was proved to be a potent partial agonist at the 42 and 62 receptors. Other 7-substituted pyrrolidinyl-benzodioxanes are under biological evaluation as well as the pyrrolidinyl-pyridodioxane stereoisomers. High 42 affinity was found for the SS stereoisomer of the opened pyrrolidinyl-pyridodioxane analogue, the pyridiyl ether of 1-(2-N-methylpyrrolidinyl)ethanol.
NUOVI LIGANDI DEI RECETTORI NICOTINICI NEURONALI: BENZODIOSSANI E PIRIDODIOSSANI 2-PIRROLIDINIL SOSTITUITI / M. Binda ; docente guida: Marco Pallavicini ; coordinatore: Carlo De Micheli. Universita' degli Studi di Milano, 2010 Dec 15. 23. ciclo, Anno Accademico 2010.
NUOVI LIGANDI DEI RECETTORI NICOTINICI NEURONALI: BENZODIOSSANI E PIRIDODIOSSANI 2-PIRROLIDINIL SOSTITUITI
M. Binda
2010
Abstract
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 42 and 7 subtype receptors. The moderate and subtype-selective 42 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 42 binding site. The 7-hydroxy derivative was proved to be a potent partial agonist at the 42 and 62 receptors. Other 7-substituted pyrrolidinyl-benzodioxanes are under biological evaluation as well as the pyrrolidinyl-pyridodioxane stereoisomers. High 42 affinity was found for the SS stereoisomer of the opened pyrrolidinyl-pyridodioxane analogue, the pyridiyl ether of 1-(2-N-methylpyrrolidinyl)ethanol.File | Dimensione | Formato | |
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