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Stereoselectivity of (R)‐ and (S)‐hexahydro‐difenidol binding to neuroblastoma M 1 , cardiac M 2 , pancreatic M 3 , and striatum M 4 muscarinic receptors
Author(s) -
Waelbroeck M.,
Camus J.,
Tastenoy M.,
Mutschler E.,
Strohmann C.,
Tacke R.,
Lambrecht G.,
Christophe J.
Publication year - 1991
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.530030207
Subject(s) - chemistry , muscarinic acetylcholine receptor , striatum , stereoselectivity , receptor , stereochemistry , medicine , biochemistry , catalysis , dopamine
(R)‐Hexahydro‐difenidol has a higher affinity for M 1 receptors in NB‐OK 1 cells, pancreas M 3 and striatum M 4 receptors (p K i 7.9 to 8.3) than for cardiac M 2 receptors (p K i 7.0). (S)‐Hexahydro‐difenidol, by contrast, is nonselective (p K i 5.8 to 6.1). Our goal in the present study was to evaluate the importance of the hydrophobic phenyl, and cyclohexyl rings of hexahydro‐difenidol for the stereoselectivity and receptor selectivity of hexahydro‐difenidol binding to the four muscarinic receptors. Our results indicated that replacement of the phenyl ring of hexahydro‐difenidol by a cyclohexyl group (→ dicyclidol) and of the cyclohexyl ring by a phenyl moiety (→ difenidol) induced a large (4‐ to 80‐fold) decrease in binding affinity for all muscarinic receptors. Difenidol had a significant preference for M 1 , M 3 , and M 4 over M 2 receptors; dicyclidol, by contrast, had a greater affinity for M 1 and M 4 than for M 2 and M 3 receptors. The binding free energy decrease due to replacement of the phenyl and the cyclohexyl groups of (R)‐hexahydro‐difenidol by, respectively, a cyclohexyl and a phenyl moiety was almost additive in the case of M 4 (striatum) binding sites. In the case of the cardiac M 2 , pancreatic M 3 , or NB‐OK 1 M 1 receptors the respective binding free energies were not completely additive. These results suggest that the four (R)‐hexahydro‐difenidol “binding moieties” (phenyl, cyclohexyl, hydroxy, and protonated amino group) cannot simultaneously form optimal interactions with the M 1 , M 2 , and M 3 muscarinic receptors. When each of the hydrophobic groups is modified, the position of the whole molecule, relative to the four subsites, was changed to allow an optimal overall interaction with the muscarinic receptor.