Archives of Pharmacal Research

  • 제17권6호
  • /
  • Pages.443-451
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  • 1994
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  • 0253-6269(pISSN)
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  • 1976-3786(eISSN)
대한약학회 (The Pharmaceutical Society of Korea)
권호 표지

Selectivity of Oxomemazine for the $M_1$ Muscarinic Receptors

  • 발행 : 1994.12.01
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초록

The binding characteristics of pirenzepine and oxomemazine to muscarinic receptor were studied to evaluate the selectivity of oxomemazine for the muscarinic receptor subtypes in rat cerebral microsomes. Equililbrium dissociation constant $(K_D){\;}of{\;}(-)[^3H]$quinuclidinyl benzilate$([^3H)QNB)$ determined from saturation isotherms was 64-pM. Analysis of the pirenzepine inghibition curve of [$^3H$]QNB binding to cerebral microsome indicatd the presence of two receptor subtypes with high $(K_1 = 16 nM, M_1 receptor)$two receptor subypes with about 20-fold difference in the affinity for high $(k_1 = 84nM, {\;} O_H receptor){\;} and {\;}low{\;} (K_1{\;} ={\;} 1.65\muM, {\;} O_L receptor$) affinity sites. The percentage populations of $M_1{\;} and M_3$, /TEX> receptors to the total receptors were 61 : 39, and those of $O_H{\;} and{\;} O_L$ receptors 39 : 61, resepectively. Both pirenzepine and oxomemazine increaed the $K_D$ value for $[^3H]QNB$ without affecting the binding site concentrations and Hii coefficient for the $[^3H]QNB$ without affecting the binding site concentractions and Hill coefficient for the [$^{3}$H]QNB binding. Oxomemazine had a 10-fold higher affinity at $M_1$ receptors than at $M_3$ receptors, and pirenzepine a 8-fold higher affinity at $O_H$ receptors were of $O_H$ receptors and 71% of $M_3$ receptors. However, $M_3$for oxomemazine and $O_H$for pirenzepine were composed of a uniform population. These results suggest that oxomemazine could be classified as a selective drug for $M_1$ receptors and also demonstrate that rat cerebral microsomes contain three different subtypes of $M_1{\;} M_3$ and the other site which is different from $M_1, {\;} M_2$, /TEX> receptors.

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참고문헌

  1. Drug evaluations annual1991 Ambre,J.J.;Bennett,D.R.;Cranston,J.W.;Dickinson,B.D.;Evans,R.M.;Glade,M.J.;Kosman,M.E.;Lampe,K.F.;McCann,M.A.;Pang,D.C.;Proudfit,C.M.;Rapoza,N.P.;Ratko,T.A.;Seidenfeld,J.;Smith,S.J.;Weaver,R.
  2. Br. J. Pharmacol. v.68 A comparison of affinity constants for muscarinic-sensitive acetylcholine receptors in guinea-pig atrial pacemaker cells at 29℃ and ileum at 37℃ Barlow,R.B.;Berry,K.J.;Glenton,P.A.M.;Nikolaou,N.M.;Soh,K.S.
  3. Br. J. Pharmacol. v.68 Three types of muscarinic receptors Barlow,R.B.;Burston,K.N.;Vis,A.
  4. Br. J. Pharmacol. v.78 The binding of muscarinic receptors in the lacrimal gland: Comparison with the cerebral cortex and myocardium Berrie,C.P.;Birdsall,N.J.M.;Burgen,A.S.V.;Hulme,E.C.
  5. J. Neurochem. v.27 Biochemical studies on muscarinic acetylcholine receptors Birdsall,N.J.M.;Hulme,E.C.
  6. Eur. J. Pharmacol. v.192 Clozapine is a potent and selective muscarinic antagonist at the five cloned human muscirinic cholinergic receptors expressed in CHO-K1 cells Bolden,C.;Cusack,B.;Richelson,E.
  7. J. Pharmacol. Exp. Ther. v.260 Antagonism by antimuscarinic and neuroleptic compounds at the five cloned human muscarinic cholinergic receptors expressed in Chinese hamster ovary cells Bolden,C.;Cusack,B.;Richelson,E.
  8. Trends Neurol. Sci. v.12 The molecular basis of muscarinic receptor density Bonner,T.I.
  9. Science v.237 Identification of a family of muscarinic acetylcholine receptor genes Bonner,T.I.;Buckley,N.J.;Young,A.C.;Brann,M.R.
  10. Neuron v.1 Cloning and expression of the human and rat $M_5$ muscarinic acetycholine receptor genes Bonner,T.I.;Young,A.C.;Brann,M.R.;Buckley,N.J.
  11. Br. J. Pharmacol. v.71 Antagonist discrimination between ganglionic and ileal muscarinic receptors Brown,D.A.;Forward,A.;Marsh,S.
  12. J. Neurosci. v.8 Localization of a family of muscarinic receptor mRNAs in rat brain Buckley,N.J.;Bonner,T.I.;Brann,M.R.
  13. Mol. Pharmacol. v.35 Antagonist binding properties of five cloned muscarinic receptors expressed in CHO-K1 cells Buckley,N.J.;Bonner,T.I.;Buckley,C.M.;Brann,M.R.
  14. Biochem. Pharmacol. v.22 Relationship between the inhibition constant($K_i$)and the concentration of inhibitor which causes 50 percent inhibition (${IC}_{50}$) of an enzymatic reaction Cheng,Y.C.;Prusoff,W.H.
  15. J. Pharmacol. Exp. Ther. v.260 Identification of multiple muscarinic blinding site subtypes in cat and human carebral vasculature Dauphin,F.;Hamel,E.
  16. J. Pharmacol. Exp.Ther. v.242 Selectivity of muscarinic antagonists in radioligand and in vivo experiments for the putative M₁,M₂and M₃receptors Doods,H.N.;Mathy,M.J.;Davidesko,D.;Van,Charldorp.K.J.;De,Jonge,A.;Van,Zwieten,P.A.
  17. Br. J. Pharmacol. v.96 Affinity of muscarinic receptor antagonists for three putative muscarinic receptor binding sites Delmondo,R.E.;Michel,A.D.;Whiting,R.L.
  18. J. Pharmacol. Exp. Ther v.256 Antagonist binding profiles of five cloned human muscarinic receptor subtypes Dorje,F.;Wess,J.;Lambrecht,G.;Tacke,R.;Mutschler,E.;Brann,M.R.
  19. Eur. J. Pharmacol. v.131 Competitive interation of pirenzepine with rat brain muscarinic acetylcholine receptors El-Fakahany,E.E.;Cioffi,C.L.;Abdellatif,M.M;Miller,M.M.
  20. Life Sci. v.38 Cardioselective profile of AF-DX 116, a muscarinic M₂receptor antagonist Giachetti,A.;Micheletti,R.;Montagna,E.
  21. Life Sci. v.40 Distribution of muscarinic receptor subtypes in rat brain as determined in binding studies with AF-DX 116 and pirenzepine Giraldo,E.;Hammer,R.;Ladinsky,H.
  22. Gastroenterology v.74 Neurohumoral, hormonal, and drug receptors for the lower esophageal sphincter Goyal,R.K.;Rattan,S.
  23. Scand. J. Gastroenterol v.15 no.sup.66 Muscarinic receptors in the stomach Hammer,R.
  24. Nature (Lond.) v.283 Pirenzepine distinguishes between different subclasses of muscarinic receptors Hammer,R.;Berrie,C.P.;Birdsall,N.J.M.;Burgen,A.S.V.;Hulme,E.C.
  25. Life Sci. v.31 Muscarinic receptor subtype: M₁and M₂biochemical and functional characterization Hammer,R.;Giachetti,A.
  26. Trends Pharmacol. Sci. v.5 Selective muscarinic receptor antagonists Hammer,R.;Giachetti,A.
  27. Life Sci. v.38 Binding profile of a novel cardioselective muscarinic receptor antagonist, AF-DX 116 to membrance of peripheral tissues and brain in the rat Hammer,R.;Giraldo,E.;Shiavi,G.B.;Monferini,E.;Ladinsky,H.
  28. Trends Pharmacol. Sci v.5 no.suppl. Subtypes of muscarinic receptors Hirschowitz,B.I.R.;Hammer,R.;Giachetti,A.;Kierns,J.J;Levine,R.R.
  29. Mol. Pharmacol. v.15 Characterization of muscarinic acetycholine receptors from mouse brain: evidence for regional heterogeneity and isomerization Kloog,Y.;Egozi,Y.;Sokolovskey,M.
  30. Br. J. Pharmacol. v.98 Functional and binding studies with muscarinic M₂subtype selective antagonists Lazareno,S.;Roberts,F.F.
  31. Yakhak Hoeji v.34 no.4 Interaction of antihistaminics with muscarinic receptor (Ⅱ): Action on the cerebral muscarinic M₁receptor Lee,S.W.;Park,Y.J.;Park,I.S.;Lee.J.S.
  32. Korean J. Pharmacol. v.30 Binding profiles of oxomemazine to the muscarinic receptor subtypes Lee,S.W.;Kim,J.G.
  33. J. Biol. Chem. v.193 Protein measurement with the Folin phenol reagent Lowry,O.H.;Rosebrough,N.J.;Farr,A.L.;Randall,R.J.
  34. J. Pharmacol. Exp. Ther. v.228 Comparison of [³H] pirenzepine and [³H]quinuclidinylbenzilate binding to muscarinic cholinergic receptors in rat brain Luthin,G.R.;Wolfe,B.B.
  35. J. Pharmacol. Exp. Ther. v.241 AF-DX 116, a cardioselective muscarinic antagonist Micheletti,R.;Montagna,E.;Giachetti,A.
  36. Eur. J. Pharmacol. v.145 Methoctramine reveals heterogeneity of M₂muscarinic receptors in longitudinal ileal smooth muscle membranes Michel,A.D.;Whiting,R.L.
  37. Anal. Biochem. v.107 LIGAND: A versitile computerized approach for characterization of ligand-binding systems Munson,P.J.;Rodbard.D.
  38. EMBO J. v.6 Distinct primary structures, ligand binding properties and tissue specific expression of four human muscarinic acetylcholine receptors Peralta,E.G.;Ashkenazi,A.;Winslow,J.W.;Smith,D.H.;Ramachandran,J.;Caron,D.
  39. Ann. N. Y. Acad. Sci. v.51 The attractions of proteins for small molecules and ions Scatchard,G.
  40. Life Sci. v.32 A unique regulatory profile and regional districution of [³H]pirenzepine binding in the rat provide evidence for distinct M₁and M₂muscarinic receptor subtypes. Watson,M.;Yamamura,H.I.;Roeske,W.R.
  41. Br. J. Pharmacol. v.102 Selectivity profile of the novel muscarinic antagonist UH-AH 37 determined by the use of cloned receptors and isolated tissue preparations Wess,J.;Lambrecht,G.;Mutschler,E.;Brann,M.R.;Dorje,F.