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

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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. 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.