Presynaptic muscarinic receptors mediating inhibition of neurogenic contractions in rabbit vas deferens are of the ganglionic M1-type

Eltze, Manfrid; Gmelin, G.; Wess, Jürgen; Strohmann, Carsten; Tacke, Reinhold; Mutschler, E.; Lambrecht, Günter

doi:10.1016/0014-2999(88)90072-6

Cited by 58 publications

(31 citation statements)

References 20 publications

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“…The affinities obtained at uterine muscarinic receptors of immature guinea-pigs were compared to those determined at M 1 (rabbit vas deferens), M 2 (guinea-pig atria) and M 3 receptors (guinea-pig ileum). The antimuscarinic potencies of the antagonists at Mb M2 and M 3 receptors (pArvalues, Table 1) werein good agreement with their affinity estimates determined in radioligand binding studies (Lazareno and Roberts 1989;Waelbroeck et al 1989) and previous functional studies (Barlow et al 1976;Gilani and Cobbin 1986;Micheletti et al 1987;Eltze 1988;Eltze et al 1988;Waelbroeck et al 1989;. A comparison of these affinity values with those determined at uterine muscarinic receptors suggests that the muscarinic receptor mediating contractions of the guinea-pig uterus is pharmacologically unique ( Table 1 ).…”

Section: Discussionsupporting

confidence: 80%

Novel pharmacological profile of muscarinic receptors mediating contraction of the guinea-pig uterus

Dörje

Friebe

Tacke

et al. 1990

Naunyn-Schmiedeberg's Arch Pharmacol

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Summary. The present study was designed to further characterize the muscarinic receptors mediating contraction of the guinea-pig uterus. The affinities of various selective muscarinic antagonists were determined and compared with those obtained at M 1 (rabbit vas deferens), M 2 (guinea-pig atria) and M 3 receptors (guinea-pig ileum).The contractile responses of uterine smooth muscle from immature guinea-pigs to carbachol (pD 2 = 5.73)were competitively antagonized by pirenzepine (pA 2 = 7.04), AF-DX 116diazepin-6-one) (pA 2 = 6.96), himbacine (pA 2 = 7.92), methoctramine (pA 2 = 7.52), 4-DAMP (4-diphenylacetoxy-N-methylpiperidine methiodide) (pA 2 = 8.87) and sila-hexocyclium (pA 2 = 8.81). A comparison of affinity values indicates that the muscarinic receptors present in guinea-pig uterus display a novel pharmacological profile which is not consistent with the presence of either an M 1 , M 2 or M 3 receptor. The affinities determined for the different antagonists rather showed a close similarity to those obtained at muscarinic receptors present in rat striatum and NG108-15 cells which are considered pharmacological equivalents (M 4 receptors) of the m4 gene product. We thus hypothesize that the guinea-pig isolated uterus preparation may serve as a simple functional assay system to study the pharmacology of M 4 receptors.

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Section: Discussionsupporting

confidence: 80%

Novel pharmacological profile of muscarinic receptors mediating contraction of the guinea-pig uterus

Dörje

Friebe

Tacke

et al. 1990

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Eglen and Whiting, 1986;Mitchelson, 1988;Mutschier et al, 1988). M 1 -receptors are found in high density in neuronal tissues such as autonotnie ganglia, cerebral cortex.…”

Section: Lntroductionmentioning

confidence: 99%

“…2) was discovered in the course of structure-activity (selectivity) relationship studies of a series of difenidol and sila-difenidol analogues ( fig. 1) (for recent reviews, see Tacke and Becker, 1987;Mutschier et al, 1988). Structurally, these molecules consist of a central carbinol (silanol) carbon (silicon) atom carrying an OH group, two ring systems and an aminoalkyl group [(CH 2 ) 0 -NR 2 ] (figs.…”

Section: Lntroductionmentioning

confidence: 99%

Affinity profiles of hexahydro-sila-difenidol analogues at muscarinic receptor subtypes

Lambrecht

Feifel

Wagner-Röder

et al. 1989

European Journal of Pharmacology

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103

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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 M 1 -(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: M 1 = M 3 > M 2 • A different selectivity patternwas observed for p-fluoro-hexahydro-sila-difenidol: M 3 > M 1 > M 2 • This compound exhibited its highest affinity for M 3 -receptors in guinea-pig ileum (pA 2 = 7.84), intermediate affinity for M 1 -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 (M 1 ), atria (M 2 ) and ileum (M 3 ) of the rat. Furthermore, dose ratios obtained with either pirenzepine (Mt) or hexahydrosila-difenidol (M 2 and M 3 ) 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.

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“…At least three different muscarinic receptor subtypes have been proposed on the basis of different affinities for antagonists such as pirenzepine (Hammer and Giachetti, 1982), methoctramine (Melchiorre, 1988;Melchiorre et al, 1987), AF-DX 116 (Micheletti et al, 1987) and bexahydro-sila-difenidol as weil as sila-hexocyclium (SiHC; Lambrecht et al, 1988;Eltze et al, 1988;Waelbroeck et al, in press). The subtypes have been termed M 1 (neuronal type), M 2 (M 2 a; cardiac type) and M 3 (M 2 p smooth musclejglandular type) receptors (for recent reviews see Mitchelson, 1988;Melchiorre, 1988;Mutschier et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

“…The subtypes have been termed M 1 (neuronal type), M 2 (M 2 a; cardiac type) and M 3 (M 2 p smooth musclejglandular type) receptors (for recent reviews see Mitchelson, 1988;Melchiorre, 1988;Mutschier et al, 1988). Five receptor subtypes were identified by molecular cloning studies and were found to be the products of distinct genes.…”

Section: Introductionmentioning

confidence: 99%

Muscarinic receptor subtypes in rat pancreatic islets: binding and functional studies

Verspohl

Tacke

Mutschler

et al. 1990

European Journal of Pharmacology

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Cholinergie agents arepotent modulators of insulin release that aet via musearinie reeeptors. We now investigated the musearlnie 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. The high-affinity Kds 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 MI 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 panereatie islets.

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Presynaptic muscarinic receptors mediating inhibition of neurogenic contractions in rabbit vas deferens are of the ganglionic M1-type

Cited by 58 publications

References 20 publications

Novel pharmacological profile of muscarinic receptors mediating contraction of the guinea-pig uterus

Novel pharmacological profile of muscarinic receptors mediating contraction of the guinea-pig uterus

Affinity profiles of hexahydro-sila-difenidol analogues at muscarinic receptor subtypes

Muscarinic receptor subtypes in rat pancreatic islets: binding and functional studies

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