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Stereoselectivity of (R)- and (S)-hexahydro-difenidol binding to neuroblastoma M1, cardiac M2, pancreatic M3, and striatum M4 muscarinic receptors.

Abstract
(R)-Hexahydro-difenidol has a higher affinity for M1 receptors in NB-OK 1 cells, pancreas M3 and striatum M4 receptors (pKi 7.9 to 8.3) than for cardiac M2 receptors (pKi 7.0). (S)-Hexahydro-difenidol, by contrast, is nonselective (pKi 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 M1, M3, and M4 over M2 receptors; dicyclidol, by contrast, had a greater affinity for M1 and M4 than for M2 and M3 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 M4 (striatum) binding sites. In the case of the cardiac M2, pancreatic M3, or NB-OK 1 M1 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 M1, M2, and M3 muscarinic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
AuthorsM Waelbroeck, J Camus, M Tastenoy, E Mutschler, C Strohmann, R Tacke, G Lambrecht, J Christophe
JournalChirality (Chirality) Vol. 3 Issue 2 Pg. 118-23 ( 1991) ISSN: 0899-0042 [Print] United States
PMID1863523 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Piperidines
  • Receptors, Muscarinic
  • dicyclidol
  • hexahydrodifenidol
  • diphenidol
Topics
  • Animals
  • Binding, Competitive
  • Corpus Striatum (ultrastructure)
  • Humans
  • Male
  • Myocardium (ultrastructure)
  • Neuroblastoma (ultrastructure)
  • Pancreas (ultrastructure)
  • Piperidines (metabolism)
  • Rats
  • Rats, Inbred Strains
  • Receptors, Muscarinic (classification, metabolism)
  • Stereoisomerism

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