TY - JOUR
T1 - Stereoselective inhibition of muscarinic receptor subtypes by the eight stereoisomers related to rociverine
AU - Barbier, Pascaline
AU - Renzetti, Anna R.
AU - Turbanti, Luigi
AU - Di Bugno, Cristina
AU - Fornai, Francesco
AU - Vaglini, Francesca
AU - Maggio, Roberto
AU - Corsini, Giovanni U.
PY - 1995/7/18
Y1 - 1995/7/18
N2 - The chemical structure corresponding to 1-hydroxy[1,1′-bicyclohexyl]-2-carboxylic acid 2-(diethylamino)-1-methylethyl ester has the classical profile of ester-type antimuscarinic drugs. The presence of three chiral carbons leads to eight stereoisomers and the substitutions on the cyclohexyl ring generate cis-isomers (1, named rociverine and trans-isomers (2). The aim of this study was to determine the binding pattern of the eight stereoisomers and two derived compounds, (1S,2S)-1-hydroxy[1,1′-bicyclohexyl]-2-carboxylic acid 2-(dimethylamino)-1-ethyl ester (3) and (1S,2S)-1-hydroxy[1,1′-bicyclohexyl]-2-carboxylic acid (S)-2-(diethylamino)-1-methylethyl ester methyl iodide (4), at the five cloned muscarinic receptors stably expressed in chinese hamster ovary cells, in order to define how stereochemical modifications could affect the affinity. Our data showed that cis-stereoisomers exhibited higher variations in affinity than trans-stereoisomers. Among the cis-stereoisomers, those with the (1R,2R) configuration showed considerably higher affinities (up to 240-fold) than those with the (1S,2S) configuration. The (1S,2S) configuration was important for binding selectivity; this was confirmed also by the use of the two additional compounds.
AB - The chemical structure corresponding to 1-hydroxy[1,1′-bicyclohexyl]-2-carboxylic acid 2-(diethylamino)-1-methylethyl ester has the classical profile of ester-type antimuscarinic drugs. The presence of three chiral carbons leads to eight stereoisomers and the substitutions on the cyclohexyl ring generate cis-isomers (1, named rociverine and trans-isomers (2). The aim of this study was to determine the binding pattern of the eight stereoisomers and two derived compounds, (1S,2S)-1-hydroxy[1,1′-bicyclohexyl]-2-carboxylic acid 2-(dimethylamino)-1-ethyl ester (3) and (1S,2S)-1-hydroxy[1,1′-bicyclohexyl]-2-carboxylic acid (S)-2-(diethylamino)-1-methylethyl ester methyl iodide (4), at the five cloned muscarinic receptors stably expressed in chinese hamster ovary cells, in order to define how stereochemical modifications could affect the affinity. Our data showed that cis-stereoisomers exhibited higher variations in affinity than trans-stereoisomers. Among the cis-stereoisomers, those with the (1R,2R) configuration showed considerably higher affinities (up to 240-fold) than those with the (1S,2S) configuration. The (1S,2S) configuration was important for binding selectivity; this was confirmed also by the use of the two additional compounds.
KW - Binding affinity
KW - CHO (Chinese hamster ovary) cells
KW - Muscarinic receptors
KW - Pirenzepine
KW - Stereoselectivity
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U2 - 10.1016/0922-4106(95)90024-1
DO - 10.1016/0922-4106(95)90024-1
M3 - Article
C2 - 8575526
AN - SCOPUS:0028982084
VL - 290
SP - 125
EP - 132
JO - European Journal of Pharmacology - Molecular Pharmacology Section
JF - European Journal of Pharmacology - Molecular Pharmacology Section
SN - 0922-4106
IS - 2
ER -