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Stereoselective interaction of trihexyphenidyl and related compounds with muscarinic receptors
Vol. 64, Nos. 617, 1999
Abstracts
593
78 STEREOSELECTIVE INTERACTION OF TRIEEXYPHENIDYL AND RELATED COMPOUNDS WlTEl MUSCARUVIC RECEPTORS J. Gross, 0. F’faff, D. Reichel*, R. Tacke*, A. Leis”, K. RGhhnann’, M. Waelbroeck+, E. Mutschler and G. Lambrecht. Dept. of Pharmacology, univ. of D-60439 Frankfurt/M., *Dept. of Ino ‘c Chemistry, Univ. of D-97074 W&burg, ‘Dept. of Chemistry, Univ. of D-01069 Dresden, Germany, % ofBiochemistry, Free univ. c&B1070 Brussels, Belgium. The enantiomers of the antiparkinsonian drug, trihexyphmidyl (THP), exhibit high stereoselectivity (up to 400-fold) at muscarinic receptors, the o-isomer being the eutomer with a selectivity profile of [email protected]: 9.0) = M4(8.8) > M3(8.1) > M (7.7) (Waelbroeck et al., EJP-MPS 227: 33, 1992). In this study, the momefs of compounds related to &rJ were investigated for their affinities at Ml-M4 receptors. In order to obtam information on the stereoselective interaction of these compounds with muscarmic recqtor~, we replaced the phenyl or the cyclohexyl ring by a cyclohexyl or a phenyl ring, respectively (+ adural diphenyl and dicyclohexyl analogues). The affinities (PA or pK values) were determined in functional assays at Ml-like (rabbit vas deferens), M2 (guinea-pig atna.? and d 3 receptors (guinea-pig ileum) as well as in radohgand receptors (rat striatum). All compounds behaved as competitive antagonists. Exchange decreased affinity (up to 200-fold), s)ervseachiral diphenyl and dicyclohexyl denvatives the corresponding eutomers of THP and of the CH OH analogue, but higher afIinities than the corresponding distomers. The sums of the affinity differences f&2( eutomer)-pA2(diphenyl)]+[pA2(eutomer)-pA2(dicyc~ohe ~11 were very similar to the experimentally obtained eudismic indices %AZ(eutomer -PAZ distomer I. With regard to Site 1 the concept of the four-binding-site mo d el OlfaelbroecL et al. EJP-MPS 189: 135. 1990). these results su!uzest that the stereoselective interaction of the enan&omeG with an OH oy CH2OH group is based on opposite binding to site 1 and site 2 by the phenyl and cyclohexyl ring. In contrast, the diphenyl analogue of THP with a CONH2 instead of the OH moiety (fenpipramide) displayed up to 220-fold higher aRinities than the corre spending eutomer (phenylkyclohexyl-type), a binding behaviour, which could not be explained by the concept of the four-binding-site model. It is suggested that these amides interact with other subsites of muscarinic Interactionof (R)-TEP (n-0) and supp. by DFG mmlopes with muscarinic receptor5 receptors than THP and its CH2OH analogue.
Abstracts
593
78 STEREOSELECTIVE INTERACTION OF TRIEEXYPHENIDYL AND RELATED COMPOUNDS WlTEl MUSCARUVIC RECEPTORS J. Gross, 0. F’faff, D. Reichel*, R. Tacke*, A. Leis”, K. RGhhnann’, M. Waelbroeck+, E. Mutschler and G. Lambrecht. Dept. of Pharmacology, univ. of D-60439 Frankfurt/M., *Dept. of Ino ‘c Chemistry, Univ. of D-97074 W&burg, ‘Dept. of Chemistry, Univ. of D-01069 Dresden, Germany, % ofBiochemistry, Free univ. c&B1070 Brussels, Belgium. The enantiomers of the antiparkinsonian drug, trihexyphmidyl (THP), exhibit high stereoselectivity (up to 400-fold) at muscarinic receptors, the o-isomer being the eutomer with a selectivity profile of [email protected]: 9.0) = M4(8.8) > M3(8.1) > M (7.7) (Waelbroeck et al., EJP-MPS 227: 33, 1992). In this study, the momefs of compounds related to &rJ were investigated for their affinities at Ml-M4 receptors. In order to obtam information on the stereoselective interaction of these compounds with muscarmic recqtor~, we replaced the phenyl or the cyclohexyl ring by a cyclohexyl or a phenyl ring, respectively (+ adural diphenyl and dicyclohexyl analogues). The affinities (PA or pK values) were determined in functional assays at Ml-like (rabbit vas deferens), M2 (guinea-pig atna.? and d 3 receptors (guinea-pig ileum) as well as in radohgand receptors (rat striatum). All compounds behaved as competitive antagonists. Exchange decreased affinity (up to 200-fold), s)ervseachiral diphenyl and dicyclohexyl denvatives the corresponding eutomers of THP and of the CH OH analogue, but higher afIinities than the corresponding distomers. The sums of the affinity differences f&2( eutomer)-pA2(diphenyl)]+[pA2(eutomer)-pA2(dicyc~ohe ~11 were very similar to the experimentally obtained eudismic indices %AZ(eutomer -PAZ distomer I. With regard to Site 1 the concept of the four-binding-site mo d el OlfaelbroecL et al. EJP-MPS 189: 135. 1990). these results su!uzest that the stereoselective interaction of the enan&omeG with an OH oy CH2OH group is based on opposite binding to site 1 and site 2 by the phenyl and cyclohexyl ring. In contrast, the diphenyl analogue of THP with a CONH2 instead of the OH moiety (fenpipramide) displayed up to 220-fold higher aRinities than the corre spending eutomer (phenylkyclohexyl-type), a binding behaviour, which could not be explained by the concept of the four-binding-site model. It is suggested that these amides interact with other subsites of muscarinic Interactionof (R)-TEP (n-0) and supp. by DFG mmlopes with muscarinic receptor5 receptors than THP and its CH2OH analogue.