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  - Binding affinities of hexahydro-difenidol and hexahydro-sila-difenidol analogues at four muscarinic receptor subtypes: constitutional and stereochemical aspects
N2  - Hexahydro-sila-difenidoJ and eight analogues behaved as simple cumpetitive inhibitors of eHJN·methyl·scopoJamine binding to homogenates frorn human neuroblastoma NB-OK 1 cells (M\(_1\) sites), rat heart (M\(_2\) sites), rat pancreas (M\(_3\) sites), and rat striatum 'B' sites (M\(_4\) sites). Pyrrolidino- and hexamethyleneimino analogues showed the same sekctivity profile as the parent compound. Hexahydro-sila-difenidol methiodide and the methiodide of p-fluoro-hexahydro·sila-difenidol had a fügher affinity but a lower selectivity than the tertiary amines. Compounds containing a p·methoxy, p-chJoro or p-fluoro substituent in the phenyl ring of hexahydro-sila-difenidol showed a qualitative)y similar selectivity profile as the parent compound (i.e., M\(_1\)= M\(_3\) = M\(_4\) >M\(_2\) ), but up to 16-fold lower affinities. o-Methoxy-hexahydro-sila-difenidol has a lower affinity than hexahydro-sila-difeni.:!o! at the four binding sites. lts selectivity profile (M\(_4\) > M\(_1\), M\(_3\) > M\(_2\) ) was different from hexahydro-sila-difenidol. Replacement of the centrat silicon atom of hexahydro-sila-difenidol, p-fluoro-hexahydro-sila-difenidol and thdr quatemary (N-methylated) analogues by a carbon atom did not change their binding affinities significantly. The iour muscarinic receptors showed a higher affinity for the (R)- than for the (S)-enantiomers of hexahydro-difenidol, p-fluorohexahydro-difenidol and their methiodides. The stereoselectivity varied depending on the receptor subtype and drug considered.
KW  - Anorganische Chemie
KW  - Muscarinic receptor antagonists (selective)
KW  - Hexahydro-sila-difenidol analogues
KW  - p-Fluoro-hexahydro-sila-difenidol
KW  - Stereoselectivity
Y1  - 1991
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-64128
ER  - 
TY  - JOUR
A1  - Lambrecht, G.
A1  - Feifel, R.
A1  - Wagner-Röder, M.
A1  - Strohmann, C.
A1  - Zilch, H.
A1  - Tacke, Reinhold
A1  - Waelbroeck, M.
A1  - Christophe, J.
A1  - Boddeke, H.
A1  - Mutschler, E.
T1  - Affinity profiles of hexahydro-sila-difenidol analogues at muscarinic receptor subtypes
N2  - In an attempt to assess the structural requirements of hexahydro-sila-difenidol for potency and selectivity, a series of analogues modified in the amino group and the phenyl ring were investigated for their affinity to muscarinic M1- (rabbit vas deferens), Mr (guinea-pig atria) and Mr (guinea-pig ileum) receptors. All compounds were competitive antagonists in the three tissues. Their affinities to the three muscarinic receptor subtypes differed by more than two orders of magnitude and the observed receptor selectivities were not associated with high affinity. The pyrrolidino and hexamethyleneimino analogues, compounds substituted in the phenylring with a methoxy group or a chlorine atom as weil as p-fluoro-hexahydro-difenidol displayed the same affinity profile as the parent compound, hexahydro-sila-difenidol: M1 = M3 > M2 • A different selectivity patternwas observed for p-fluoro-hexahydro-sila-difenidol: M3 > M1 > M2 • This compound exhibited its highest affinity for M3-receptors in guinea-pig ileum (pA 2 = 7.84), intermediate affinity for M1-receptors in rabbit vas deferens (pA 2 = 6.68) and lowest affinity for the Mrreceptors in guinea-pig atria (pA 2 = 6.01). This receptor selectivity profile of p-fluoro-hexahydro-sila-difenidol was confirmed in ganglia (M1), atria (M2 ) and ileum (M 3 ) of the rat. Furthermore, dose ratios obtained with either pirenzepine (Mt) or hexahydrosila- difenidol (M2 and M3) and the p-fluoro analogue used in combination suggested that the antagonism was additive, implying mutual competition with a single population of muscarinic receptor subtypes. These results indicate that p-fluoro-hexahydro-sila-difenidol represents a valuable tool for characterization of muscarinic receptor subtypes.
KW  - Anorganische Chemie
KW  - Muscarinic receptor subtypes
KW  - Muscarinic M3selective antagonists
KW  - Hexahydro-sila-difenidol analogues
Y1  - 1989
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63979
ER  -