Stereoselective inhibition of muscarinic receptor subtypes by the eight stereoisomers related to rociverine.
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) (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.
Barbier
P
P
Institute of Pharmacology School of Medicine, University of Pisa, Italy.
Renzetti
A R
AR
Turbanti
L
L
Di Bugno
C
C
Fornai
F
F
Vaglini
F
F
Maggio
R
R
Corsini
G U
GU
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D005260:Female; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D019832:N-Methylscopolamine; D010276:Parasympatholytics / Q000494:pharmacology*; D010890:Pirenzepine / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000145:classification / Q000187:drug effects / Q000378:metabolism; D012602:Scopolamine Derivatives / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection
D003509:Cyclohexanecarboxylic Acids; D018727:Muscarinic Antagonists; D010276:Parasympatholytics; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; D010890:Pirenzepine; D019832:N-Methylscopolamine; C021082:rociverine