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  - 
TY  - JOUR
A1  - Polidori, C.
A1  - Massi, M.
A1  - Lambrecht, G.
A1  - Mutschler, E.
A1  - Tacke, Reinhold
A1  - Melchiorre, C.
T1  - Selective antagonists provide evidence that M\(_1\) muscarinic receptors may mediate carbachol-induced drinking in the rat
N2  - The present study served to investigate the ability of seven selective muscarinic antagonists to inhibit carbachol-induced drinking in the rat. The muscarinic antagonists were given by intracerebroventricular (i.c.v.) injection 1 min before the i.c.v. injection of carbachol (1 \(\mu\)g/rat). The M\(_2\) antagonist, methoctramine, was inactive up to 80.3 nmol/rat. The M\(_3\) antagonist, p-fluoro-hexahydro-sila-difenidol, elicited a modest (42%) but statistically significant inhibition of drinking only at 80 nmol/rat. On the other band, the selective M\(_1\) antagonists, (R)-trihexyphenidyl, o-methoxy-sila-hexocyclium and pirenzepine, produced a marked and dose-dependent inhibition of carbachol-induced drinking, their 1050 values being 0.51. 7.36 and 9.31 nmoljrat. Also the M\(_1\)/M\(_3\) antagonists, 4-diphenylacetoxy-Nmethylpiperidine methiodide and hexahydro-sila-difen.idol, were potent inhibitors of carbachol-induced drinking, their ID\(_50\) values (0.28 and 11.09 nmoljrat) being related to their pA\(_2\) values for M1 receptors in rabbi t vas deferens. These data suggest that carbachol-induced drinking may be mediated by activation of muscarinic M\(_1\) receptors.
KW  - Anorganische Chemie
KW  - Carbachol-induced drinking
KW  - Muscarinic receptor antagonists
KW  - Muscarinic receptor subtypes
KW  - Muscarinic M1 receptors; Muscarinic M2 receptors
Y1  - 1990
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-64044
ER  - 
TY  - JOUR
A1  - Verspohl, E. J.
A1  - Tacke, Reinhold
A1  - Mutschler, E.
A1  - Lambrecht, G.
T1  - Muscarinic receptor subtypes in rat pancreatic islets: binding and functional studies
N2  - Cholinergie agents arepotent modulators of insulin release that aet via musearinie reeeptors. We now investigated the muscarinic receptor subtype present in rat panereatic islets in binding and funetional studies. Binding of 5 nM [ \(^3\)H]N-methylscopolamine ([\(^3\)H]NMS) was half maximal at 30 min. At 60 min, the maximal total bindingwas 1.29% and the non-specifie binding (presence of 100 ,uM atropine) was 0.18% of the total radioaetivity per 10 f.'g islet protein. Unlabelled atropine inhibited [\(^3\)H]NMS binding with an IC50 of ca. 30 nM. The rank order of antagonist high-affinity binding was atropine > sila-hexocyelium methyl sulfate (SiHC; M\(_1\) > M\(_3\) > M\(_2\) ) > pirenzepine (M\(_1\)> M\(_2\) = M\(_3\) ) = methoctramine (M\(_2\) > M\(_1\) > M\(_3\) ). The high-affinity K\(_d\)s were 8.5, 56, 1300 and 1300 nM, respectively. The high affinity Kd of the muscarinie receptor agonist, arecaidine propargyl ester (APE), was 8.1 nM. The EC\(_{50}\) for the biologieal effects of APE on insulin and glucagon secretion was 3.2 and 2.3 nM. The rank order for the high-affinity biological effects of antagonists (inhibition of APE-mediated insulin/ glucagon release) was almost the same as for binding. The data indicate that rat pancreatie islets contain neither an M\(_1\) subtype (high-affinity for pirenzepine) nor an M\(_2\) subtype (high-affinity for methoctramine) receptor. However, the data evidence an M\(_3\) receptor subtype, since SiHC in the absence of the M\(_1\) receptor subtype shows a relatively high affinity to the receptors in rat panereatic islets.
KW  - Anorganische Chemie
KW  - Muscarinic receptor subtypes
KW  - Islets of Langerhans (rat)
KW  - Insulin
KW  - Glucagon
Y1  - 1990
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63993
ER  -