BIOMAT Database Logo BIOMAT Database Logo

Stereoselective interaction of uncharged esters at four muscarinic receptor subtypes. 1996

M Waelbroeck, and X Hou, and J Wehrle, and E Mutschler, and E Van Tilburg, and W Menge, and H Timmerman, and G Lambrecht
Department of Biochemistry and Nutrition, Medical School, Université Libre de Bruxelles, Belgium. probbe@ulb.ac.be

We investigated the binding and pharmacological properties of the esters of 3,3-dimethylbutan-1-ol (the carbon analogue of choline) with either diphenylglycolic acid, (R)-phenylcyclohexylglycolic acid, or (S)-phenylcyclohexylglycolic acid [BS-6181, (R)-BS-7826 and (S)-BS-7826, respectively] at muscarinic M1, M2, M3 (Hm3) and M4 receptors. The three uncharged compounds were muscarinic receptor antagonists, with pA2 or pKi values between 7.9 and 5.6. The achiral ester BS-6181 displayed highest affinity for M1, M3 (Hm3) and M4 receptors (pA2 or pKi = 7.2-7.6) and lower affinity for M2 receptors (pA2 or pKi = 6.7 and 6.8). The four muscarinic receptor subtypes were able to distinguish between the two enantiomers of the cyclohexyl derivative of BS-6181 [(R)- and (S)-BS-7826], with a preference for the (R)-isomer (up to 79-fold). Interestingly, the (S)-enantiomer of BS-7826, being the distomer, was found to be M4 selective (pKi/M4 = 6.9; pA2 or pKi/M1-M3 (Hm3) = 5.6-6.2). These results indicate that uncharged compounds may (stereo)selectively bind to muscarinic receptors via hydrophobic interactions. Thus, an ionic bond between muscarinic ligands and an anionic site of the receptor is not absolutely necessary for recognition of muscarinic receptors.

UI MeSH Term Description Entries
D008297 Male Males
D011817 Rabbits A burrowing plant-eating mammal with hind limbs that are longer than its fore limbs. It belongs to the family Leporidae of the order Lagomorpha, and in contrast to hares, possesses 22 instead of 24 pairs of chromosomes. Belgian Hare,New Zealand Rabbit,New Zealand Rabbits,New Zealand White Rabbit,Rabbit,Rabbit, Domestic,Chinchilla Rabbits,NZW Rabbits,New Zealand White Rabbits,Oryctolagus cuniculus,Chinchilla Rabbit,Domestic Rabbit,Domestic Rabbits,Hare, Belgian,NZW Rabbit,Rabbit, Chinchilla,Rabbit, NZW,Rabbit, New Zealand,Rabbits, Chinchilla,Rabbits, Domestic,Rabbits, NZW,Rabbits, New Zealand,Zealand Rabbit, New,Zealand Rabbits, New,cuniculus, Oryctolagus
D011976 Receptors, Muscarinic One of the two major classes of cholinergic receptors. Muscarinic receptors were originally defined by their preference for MUSCARINE over NICOTINE. There are several subtypes (usually M1, M2, M3....) that are characterized by their cellular actions, pharmacology, and molecular biology. Muscarinic Acetylcholine Receptors,Muscarinic Receptors,Muscarinic Acetylcholine Receptor,Muscarinic Receptor,Acetylcholine Receptor, Muscarinic,Acetylcholine Receptors, Muscarinic,Receptor, Muscarinic,Receptor, Muscarinic Acetylcholine,Receptors, Muscarinic Acetylcholine
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D004952 Esters Compounds derived from organic or inorganic acids in which at least one hydroxyl group is replaced by an –O-alkyl or another organic group. They can be represented by the structure formula RCOOR’ and are usually formed by the reaction between an acid and an alcohol with elimination of water. Ester
D006168 Guinea Pigs A common name used for the genus Cavia. The most common species is Cavia porcellus which is the domesticated guinea pig used for pets and biomedical research. Cavia,Cavia porcellus,Guinea Pig,Pig, Guinea,Pigs, Guinea
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001665 Binding Sites The parts of a macromolecule that directly participate in its specific combination with another molecule. Combining Site,Binding Site,Combining Sites,Site, Binding,Site, Combining,Sites, Binding,Sites, Combining
D013237 Stereoisomerism The phenomenon whereby compounds whose molecules have the same number and kind of atoms and the same atomic arrangement, but differ in their spatial relationships. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 5th ed) Molecular Stereochemistry,Stereoisomers,Stereochemistry, Molecular,Stereoisomer
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships

Related Publications

M Waelbroeck, and X Hou, and J Wehrle, and E Mutschler, and E Van Tilburg, and W Menge, and H Timmerman, and G Lambrecht
The existence of stable enantiomers of telenzepine and their stereoselective interaction with muscarinic receptor subtypes.
April 1989, Molecular pharmacology,
M Waelbroeck, and X Hou, and J Wehrle, and E Mutschler, and E Van Tilburg, and W Menge, and H Timmerman, and G Lambrecht
Stereoselective recognition of the enantiomers of phenglutarimide and of six related compounds by four muscarinic receptor subtypes.
December 1996, British journal of pharmacology,
M Waelbroeck, and X Hou, and J Wehrle, and E Mutschler, and E Van Tilburg, and W Menge, and H Timmerman, and G Lambrecht
On the interaction of gallamine with muscarinic receptor subtypes.
July 1990, European journal of pharmacology,
M Waelbroeck, and X Hou, and J Wehrle, and E Mutschler, and E Van Tilburg, and W Menge, and H Timmerman, and G Lambrecht
Muscarinic receptor subtypes.
January 1990, Annual review of pharmacology and toxicology,
M Waelbroeck, and X Hou, and J Wehrle, and E Mutschler, and E Van Tilburg, and W Menge, and H Timmerman, and G Lambrecht
[Muscarinic receptor subtypes].
July 1992, Pharmazie in unserer Zeit,
M Waelbroeck, and X Hou, and J Wehrle, and E Mutschler, and E Van Tilburg, and W Menge, and H Timmerman, and G Lambrecht
Interaction of ebeinone, an alkaloid from Fritillaria imperialis, at two muscarinic acetylcholine receptor subtypes.
January 1997, Life sciences,
M Waelbroeck, and X Hou, and J Wehrle, and E Mutschler, and E Van Tilburg, and W Menge, and H Timmerman, and G Lambrecht
Stereoselective inhibition of muscarinic receptor subtypes by the eight stereoisomers related to rociverine.
July 1995, European journal of pharmacology,
M Waelbroeck, and X Hou, and J Wehrle, and E Mutschler, and E Van Tilburg, and W Menge, and H Timmerman, and G Lambrecht
The interaction of hexamethonium with muscarinic receptor subtypes in vitro.
October 1989, British journal of pharmacology,
M Waelbroeck, and X Hou, and J Wehrle, and E Mutschler, and E Van Tilburg, and W Menge, and H Timmerman, and G Lambrecht
Pharmacological muscarinic receptor subtypes.
January 1990, Progress in brain research,
M Waelbroeck, and X Hou, and J Wehrle, and E Mutschler, and E Van Tilburg, and W Menge, and H Timmerman, and G Lambrecht
Interaction of amitriptyline with muscarinic receptor subtypes in the rat brain.
January 1989, Neurochemistry international,
Copied contents to your clipboard!