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

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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 M1 (rabbit vas deferens), M2 (guinea-pig atria) and M3 receptors (guinea-pig ileum).

The contractile responses of uterine smooth muscle from immature guinea-pigs to carbachol (pD2 = 5.73) were competitively antagonized by pirenzepine (pA2 = 7.04), AF-DX 116 (11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]- 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzo. diazepin-6-one) (pA2 = 6.96), himbacine (pA2 = 7.92), methoctramine (pA2 = 7.52), 4-DAMP (4-diphenylacetoxy-N-methylpiperidine methiodide) (pA2 = 8.87) and sila-hexocyclium (pA2 = 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 M1, M2 or M3 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 (M4 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 M4 receptors.

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References

  • Akiba I, Kubo T, Maeda A, Bujor J, Nakai J, Mishina M, Numa S (1988) Primary structure of porcine muscarinic acetylcholine receptor III and antagonist binding studies. FEBS Lett 235:257–261

    Google Scholar 

  • Ashkenazi A, Peralta EG, Winslow JW, Ramachandran J, Capon DJ (1989) Functional diversity of muscarinic receptor subtypes in cellular signal transduction and growth. Trends Pharmacol Sci Suppl 10:16–22

    Google Scholar 

  • Arunlakshana O, Schild HO (1959) Some quantitative uses of drug antagonists. Br J Pharmacol 14:48–58

    Google Scholar 

  • Barlow RB, Berry KJ, Glenton PAM, Nikolaou NM, Soh KS (1976) A comparison of affinity constants for muscarinic-sensitive acetylcholine receptors in guinea-pig atrial pacemaker cells at 29°C and in ileum at 29°C and 37°C. Br J Pharmacol 58:613–620

    Google Scholar 

  • Baumgold J, White TH (1989) Pharmacological differences between muscarinic receptors coupled to phosphoinositide turnover and those coupled to adenylate cyclase inhibition. Biochem Pharmacol 38:1605–1616

    Google Scholar 

  • Bonner TI, Buckley NJ, Young AC, Brann MR (1987) Identification of a family of muscarinic acetylcholine receptor genes. Science 237:527–532

    CAS  PubMed  Google Scholar 

  • Bonner TI, Young AC, Buckley NJ (1988) Cloning and expression of the human and rat m5 muscarinic acetylcholine receptor genes. Neuron 1:403–410

    Google Scholar 

  • Brann MR, Buckley NJ, Bonner TI (1988) The striatum and cerebral cortex express different muscarinic receptor mRNAs. FEBS Lett 230:90–94

    Google Scholar 

  • Buckley NJ, Bonner TI, Buckley CM, Brann MR (1989) Antagonist binding properties of five cloned muscarinic receptors expressed in CHO-K1 cells. Mol Pharmacol 35:469–476

    Google Scholar 

  • Doods HN, Mathy M-J, Davidesko D, van Charldorp KJ, de Jonge A, van Zwieten PA (1987) Selectivity of muscarinic antagonists in radioligand and in vivo experiments for the putative M1, M2 and M3 receptors. J Pharmacol Exp Ther 242:257–262

    Google Scholar 

  • Dörje F, Friebe T, Tacke R, Mutschler E, Lambrecht G (1990) Pharmacological characterization of muscarinic receptors mediating contractions of guinea-pig uterus. Naunyn-Schmiedeberg's Arch Pharmacol 341: Suppl. R79 (abstract)

  • Eglen RM, Michel AD, Whiting RL (1989) Characterisation of the muscarinic receptor subtype mediating contractions of the guinea-pig uterus. Br J Pharmacol 96:497–499

    Google Scholar 

  • Eltze M (1988) Muscarinic M1- and M2-receptors mediating opposite effects on neuromuscular transmission in rabbit vas deferens. Eur J Pharmacol 151:205–221

    Google Scholar 

  • Eltze M, Gmelin G, Wess J, Strohmann C, Tacke R, Mutschler E, Lambrecht G (1988) Presynaptic muscarinic receptors mediating inhibition of neurogenic contraction in rabbit vas deferens are of the ganglionic M1-type. Eur J Pharmacol 158:233–242

    Google Scholar 

  • Gilani SAH, Cobbin LB (1986) The cardio-selectivity of himbacine: a muscarinic receptor antagonist. Naunyn-Schmiedeberg's Arch Pharmacol 332:16–20

    Google Scholar 

  • Giraldo E, Vigano MA, Hammer R, Ladinsky H (1988) Characterization of muscarinic receptors in guinea-pig ileum longitudinal smooth muscle. Mol Pharmacol 33:617–625

    Google Scholar 

  • Hammer R, Berrie CP, Birdsall NJM, Burgen ASV, Hulme EC (1980) Pirenzepine distinguishes between different subclasses of muscarinic receptors. Nature 283:90–92

    Google Scholar 

  • Hammer R, Giachetti A (1982) Muscarinic receptor subtypes: M1 and M2, biochemical and functional characterization. Life Sci 31:2991–2998

    Google Scholar 

  • Hammer R, Giraldo E, Schiavi GB, Montagna E, Ladinsky H (1986) Binding profile of a novel cardioselective muscarinic receptor antagonist, AF-DX 116, to membranes of peripheral tissues and brain in the rat. Life Sci 38:1653–1662

    Google Scholar 

  • Harden TK, Tanner LI, Martin MW, Nakahata N, Hughes AR, Helper JR, Evans T, Masters SB, Brown JH (1986) Characteristics of two biochemical responses to stimulation of muscarinic cholinergic receptors. Trends Pharmacol Sci Suppl. 7:14–18

    Google Scholar 

  • Lambrecht G, Feifel R, Wagner-Röder M, Strohmann C, Zilch H, Tacke R, Waelbroeck M, Christophe J, Boddeke H, Mutschler E (1989) Affinity profiles of hexahydro-sila-difenidol analogues at muscarinic receptor subtypes. Eur J Pharmacol 168:71–80

    Google Scholar 

  • Lazareno S, Roberts FF (1989) Functional and binding studies with muscarinic M2-subtype selective antagonists. Br J Pharmacol 98:309–317

    Google Scholar 

  • Leiber D, Harbon S, Guillet J-G, André C, Strosberg AD (1984) Monoclonal antibodies to purified muscarinic receptor display agonist-like activity. Proc Natl Acad Sci USA 81:4331–4334

    Google Scholar 

  • Levine RR, Birdsall NJM (eds) (1989) Subtypes of muscarinic receptors IV. Trends Pharmacol Sci Suppl 10:1–119

    Google Scholar 

  • Marc S, Leiber D, Harbon S (1986) Carbachol and oxytocin stimulate the generation of inositol phosphates in the guinea-pig myometrium. FEBS Lett 201:9–14

    Google Scholar 

  • McKinney M, Anderson D, Forray C, El-Fakahany EE (1989) Characterisation of the striatal M2 muscarinic receptor mediating inhibition of cyclic AMP using selective antagonists: a comparison with the brainstem M2 receptor. J Pharmacol Exp Ther 250:565–572

    Google Scholar 

  • Melchiorre C, Angeli P, Lambrecht G, Mutschler E, Picchio MT, Wess J (1987) Antimuscarinic action of methoctramine, a new cardioselective M2 muscarinic antagonist alone and in combination with atropine and gallamine. Eur J Pharmacol 144:117–124

    Google Scholar 

  • Micheletti R, Montagna E, Giachetti A (1987) AF-DX 116, a cardioselective muscarinic antagonist. J Pharmacol Exp Ther 241:628–634

    Google Scholar 

  • Michel AD, Delmondo R, Stefanich E, Whiting RL (1989) Binding characteristics of the muscarinic receptor subtype of the NG 108–15 cell line. Naunyn-Schmiedeberg's Arch Pharmacol 340:62–67

    Google Scholar 

  • Mitchelson F (1988) Muscarinic receptor differentiation. Pharmacol Ther 37:357–423

    Google Scholar 

  • Monferini E, Giraldo E, Ladinsky H (1988) Characterization of the muscarinic receptor subtypes in the rat urinary bladder. Eur J Pharmacol 147:453–458

    Google Scholar 

  • Moser U, Lambrecht G, Wagner M, Wess J, Mutschler E (1989) Structure-activity relationship of new analogues of arecaidine propargyl ester at muscarinic M1 and M2 receptor subtypes. Br J Pharmacol 96:319–324

    Google Scholar 

  • Mutschler E, Hultzsch K (1973) Über Struktur-Wirkungs-Beziehungen von ungesättigten Estern des Arecaidins und Dihydroarecaidins. Arzneimittelforschung 23:732–737

    Google Scholar 

  • Mutschler E, Lambrecht G (1984) Selective muscarinic agonists and antagonists in functional tests. Trends Pharmacol Sci Suppl 5:39–44

    Google Scholar 

  • Nelson WL, Freeman DS, Vinzenzi FF (1976) Stereochemical analogs of a muscarinic, ganglionic stimulant, 2. Cis and trans olefinic, epoxide, and cyclopropane analogs related to 4-[N-(3-chlorophenyl) carbamoyloxy]-2-butynyltrimethylammonium chloride (McN-A-343). J Med Chem 19:153–158

    Google Scholar 

  • Paton WDM, Zar MA (1968) The origin of acetylcholine release from guinea-pig intestine and longitudinal muscle strips. J Physiol 194:13–33

    Google Scholar 

  • Peralta EG, Ashkenazi A, Winslow JW, Smith DH, Ramachandran J, Capon DJ (1987) Distinct primary structures, ligand-binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors. EMBO J 6:3923–3929

    Google Scholar 

  • Peralta EG, Ashkenazi A, Winslow JW, Ramachandran J, Capon DJ (1988) Differential regulation of PI hydrolysis and adenylyl cyclase by muscarinic receptor subtypes. Nature 334:434–437

    Google Scholar 

  • Roffel AF, Elzinga CRS, Meurs H, Zaagsma J (1989) Allosteric interactions of three muscarinic antagonists at bovine tracheal smooth muscle and cardiac M2 receptors. Eur J Pharmacol — Mol Pharmacol Sect 172:61–70

    Google Scholar 

  • Tacke R, Linoh H, Rafeiner K, Lambrecht G, Mutschler E (1989) Synthesis and properties of the selective antimuscarinic agent sila-hexocyclium methyl sulfate. J Organomet Chem 359:159–168

    Google Scholar 

  • Tallarida RJ, Murray RB (1986) Manual of pharmacologic calculations with computer programs. Sec ed, Springer, Berlin Heidelberg New York Tokyo

    Google Scholar 

  • Waelbroeck M, Tastenoy M, Camus J, Christophe J, Strohmann C, Linoh H, Zilch H, Tacke R, Mutschler E, Lambrecht G (1989) Binding and functional properties of antimuscarinics of the hexocyclium/sila-hexocyclium and hexahydro-diphenidol/hexahydro-sila-diphenidol type to muscarinic receptor subtypes. Br J Pharmacol 98:197–205

    Google Scholar 

  • Waelbroeck M, Camus J, Tastenoy M, Christophe J (1990) Identification of the striatum “B” sites as belonging to the M4 muscarinic receptor subtype. Naunyn-Schmiedeberg's Arch Pharmacol 341: Suppl. R80 (abstract)

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  1. Frank Dörje

    Present address: Laboratory of Molecular Biology, NINDS, NIH, Bld. 36, Rm. 3D-02, 20892, Bethesda, MD, USA

Authors and Affiliations

  1. Department of Pharmacology, University of Frankfurt, Theodor-Stern-Kai 7, Gebäude 75A, D-6000, Frankfurt/M., Federal Republic of Germany

    Frank Dörje, Thomas Friebe, Ernst Mutschler & Günter Lambrecht

  2. Institute of Inorganic Chemistry, University of Karlsruhe, Engesserstrasse, D-7500, Karlsruhe, Federal Republic of Germany

    Reinhold Tacke

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  1. Frank Dörje
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  2. Thomas Friebe
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  3. Reinhold Tacke
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  4. Ernst Mutschler
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  5. Günter Lambrecht
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Dörje, F., Friebe, T., Tacke, R. et al. Novel pharmacological profile of muscarinic receptors mediating contraction of the guinea-pig uterus. Naunyn-Schmiedeberg's Arch Pharmacol 342, 284–289 (1990). https://doi.org/10.1007/BF00169439

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