Stereoselective interaction of procyclidine, hexahydro-difenidol, hexbutinol and oxyphencyclimine, and of related antagonists, with four muscarinic receptors.
We investigated the binding properties of the (R)- and (S)-enantiomers of the muscarinic antagonists trihexyphenidyl, procyclidine, hexahydro-difenidol, p-fluoro-hexahydro-difenidol, hexbutinol, p-fluoro-hexbutinol, and their corresponding methiodides at muscarinic M1, M2, M3 and M4 receptor subtypes. In addition, binding properties of the (R)- and (S)-enantiomers of oxyphencyclimine were studied. The (R)- enantiomers (eutomers) of all the compounds had a greater affinity than the (S)-isomers for the four muscarinic receptor subtypes. The binding patterns of the (R)- and (S)-enantiomers were generally different. We did not observe any general correlation between the potency of the high-affinity enantiomer and the affinity ratio (eudismic ratio) of the two enantiomers. The results are discussed in terms of a 'four subsites' binding model.
Waelbroeck
M
M
Department of Biochemistry and Nutrition, Medical School, Free University of Brussels, Belgium.
Camus
J
J
Tastenoy
M
M
Mutschler
E
E
Strohmann
C
C
Tacke
R
R
Schjelderup
L
L
Aasen
A
A
Lambrecht
G
G
Christophe
J
J
D000480:Alkynes / Q000494:pharmacology*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D019832:N-Methylscopolamine; D009447:Neuroblastoma; D010179:Pancreas / Q000187:drug effects; D010276:Parasympatholytics / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D011352:Procyclidine / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects*; D012602:Scopolamine Derivatives / Q000494:pharmacology; D013237:Stereoisomerism; D014316:Tritium
D000480:Alkynes; D010276:Parasympatholytics; D010880:Piperidines; D011743:Pyrimidines; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; D014316:Tritium; C060685:hexahydrodifenidol; C063963:hexbutinol; C100201:oxyphencyclimine; D011352:Procyclidine; D019832:N-Methylscopolamine