A series of diastereomeric 2-(2-pyrrolidinyl)-1,4-benzodioxanes bearing a small, hydrogen-bonding substituent at the 7-, 6-, or 5-position of benzodioxane have been studied for α4β2 and α3β4 nicotinic acetylcholine receptor affinity and activity. Analogous to C(5)H replacement with N and to a much greater extent than decoration at C(7), substitution at benzodioxane C(5) confers very high α4β2/α3β4 selectivity to the α4β2 partial agonism. Docking into the two receptor structures recently determined by cryo-electron microscopy and site-directed mutagenesis at the minus β2 side converge in indicating that the limited accommodation capacity of the β2 pocket, compared to that of the β4 pocket, makes substitution at C(5) rather than at more projecting C(7) position determinant for this pursued subtype selectivity.

Modifications at C(5) of 2-(2-pyrrolidinyl)-substituted 1,4-benzodioxane elicit potent α4β2 nicotinic acetylcholine receptor partial agonism with high selectivity over the α3β4 subtype / Bavo, Francesco; Pallavicini, Marco; Gotti, Cecilia; Appiani, Rebecca; Moretti, Milena; Colombo, Sara Francesca; Pucci, Susanna; Viani, Paola; Budriesi, Roberta; Renzi, Massimiliano; Fucile, Sergio; Bolchi, Cristiano. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 63:24(2020), pp. 15668-15692. [10.1021/acs.jmedchem.0c01150]

Modifications at C(5) of 2-(2-pyrrolidinyl)-substituted 1,4-benzodioxane elicit potent α4β2 nicotinic acetylcholine receptor partial agonism with high selectivity over the α3β4 subtype

Renzi, Massimiliano;Fucile, Sergio;
2020

Abstract

A series of diastereomeric 2-(2-pyrrolidinyl)-1,4-benzodioxanes bearing a small, hydrogen-bonding substituent at the 7-, 6-, or 5-position of benzodioxane have been studied for α4β2 and α3β4 nicotinic acetylcholine receptor affinity and activity. Analogous to C(5)H replacement with N and to a much greater extent than decoration at C(7), substitution at benzodioxane C(5) confers very high α4β2/α3β4 selectivity to the α4β2 partial agonism. Docking into the two receptor structures recently determined by cryo-electron microscopy and site-directed mutagenesis at the minus β2 side converge in indicating that the limited accommodation capacity of the β2 pocket, compared to that of the β4 pocket, makes substitution at C(5) rather than at more projecting C(7) position determinant for this pursued subtype selectivity.
2020
α4β2 α3β4 NAchRs Partial Agonism Patch-Clamp Computational Modeling
01 Pubblicazione su rivista::01a Articolo in rivista
Modifications at C(5) of 2-(2-pyrrolidinyl)-substituted 1,4-benzodioxane elicit potent α4β2 nicotinic acetylcholine receptor partial agonism with high selectivity over the α3β4 subtype / Bavo, Francesco; Pallavicini, Marco; Gotti, Cecilia; Appiani, Rebecca; Moretti, Milena; Colombo, Sara Francesca; Pucci, Susanna; Viani, Paola; Budriesi, Roberta; Renzi, Massimiliano; Fucile, Sergio; Bolchi, Cristiano. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 63:24(2020), pp. 15668-15692. [10.1021/acs.jmedchem.0c01150]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1471629
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