TY  - JOUR
A1  - Waelbroeck, M.
A1  - Camus, J.
A1  - Tastenoy, M.
A1  - Mutschler, E.
A1  - Strohmann, C.
A1  - Tacke, Reinhold
A1  - Lambrecht, G.
A1  - Christophe, J.
T1  - Stereoselectivity of (R)- and (S)-hexahydro-difenidol binding to neuroblastoma M\(_1\), cardiac M\(_2\), pancreatic M\(_3\), and striatum M\(_4\) muscarinic receptors
N2  - (R)-Hexahydro-difenidol has a higher affinity for M\(_1\) receptors in NB-OK 1 cells, pancreas M\(_3\) and striatum M\(_4\) receptors (pKi 7.9 to 8.3) than for cardiac M2 receptors (pKi 7 .0). (8)-Hexahydro-difenidol, by contrast, is nonselective (pKi 5.8 to 6.1). Our goal in the present study was to evaluate the importance ofthe hydrophobic phenyl, and cyclohexyl rings of hexahydro-difenidol for the stereoselectivity and reeeptor selectivity of hexahydro-difenidol binding to the four muscarinic receptors. Our results indieated that replacement of the phenyl ring of hexahydro-difenidol by a cyclohexyl group <~ dicyclidol) and ofthe cyclohexyl ring by a phenyl moiety <~ difenidol) indueed a !arge (4- to 80-fold) decrease in binding affinity for all musearlnie receptors. Difenidol had a signifieant preference for M\(_1\) , M\(_3\) , and M\(_4\) over M\(_2\) receptors; dicyclidol, by eontrast, had a greater affinity for M\(_1\) and M\(_4\) than for M\(_2\) and M\(_3\) receptors. The binding free energy deerease due to replacement ofthe phenyl and the cyelohexyl groups of(R)-hexahydro-difenidol by, respectively, a eyclohexyl and a phenyl moiety was almostadditive in the ease of M\(_4\) (striatum) binding sites. In the ease ofthe cardiac M\(_2\), pancreatic M\(_3\) , or NB-OK 1 M\(_1\) receptors the respective binding free energies were not eompletely additive. These results suggest that the four (R)-hexahydro-difenidol ''binding moieties" (phenyl, cyclohexyl, hydroxy, and protonated amino group) cannot simultaneously form optimal interaetions with the M\(_1\), M\(_2\), and M\(_3\) muscarinic receptors. When eaeh 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 musearlnie receptor.
KW  - Anorganische Chemie
KW  - hexahydro-difenidol enantiomers
KW  - muscarinic receptor subtypes
KW  - stereoselective interaction
KW  - difenidol
KW  - dicyclidol
Y1  - 1991
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-64135
ER  -