(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)