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The Pharmaceutical Society of Korea (대한약학회)
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Selectivity of Oxomemazine for the $M_1$ Muscarinic Receptors

  • Published : 1994.12.01
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Abstract

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.

Keywords

References

  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.