Glycopyrronium bromide blocks differentially responses mediated by muscarinic receptor subtypes.
To analyse the potency of glycopyrronium bromide in blocking responses mediated via subtypes of muscarinic receptors in vitro, we tried to determine its equilibrium dissociation constants at prejunctional muscarinic receptors inhibiting the twitch response of rabbit vas deferens (presumed M1 type), at M2 (paced at left atria), M3 (guinea pig ileum) muscarinic receptor subtypes and at the muscarinic receptor of the rabbit iris sphincter (not M1-M4, not m5). Glycopyrronium bromide shifted to the right the curve for inhibition of the twitch response induced by the agonist McN-A-343, and the methacholine-induced curves for inhibition of rat atrial contraction, and for tonic contraction of guinea pig ileum and rabbit iris sphincter. Glycopyrronium bromide blocked with very high potency (> 11, apparent -log KB) the response in rabbit vas deferens. Its affinity was low (9.09) for the M2 subtype, and intermediate (10.31 or 10.13) for the ileal M3 and the atypical iris muscarinic receptor subtype, respectively. Except at the receptors in rabbit vas deferens, the blockade of agonist effect appeared to be of simple competitive type. In conclusion, glycopyrronium bromide is about 10 or 100 fold more potent in preventing a response to activation of the prejunctional receptor in rabbit vas deferens than in blocking an M3 or M2 muscarinic receptor subtype, respectively, in vitro. The low affinity for M2 receptors may, in part, explain the low incidence of unwanted tachycardia in therapy. The drug failed to discriminate between an M3 receptor and the atypical rabbit iris sphincter receptor.
Fuder
H
H
Pharmakologisches Institut der Universität, Mainz, Federal Republic of Germany.
Meincke
M
M
D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride / Q000494:pharmacology; D000818:Animals; D005260:Female; D006024:Glycopyrrolate / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007498:Iris / Q000187:drug effects; D008297:Male; D008688:Methacholine Compounds / Q000494:pharmacology; D008954:Models, Biological; D018727:Muscarinic Antagonists; D009130:Muscle, Smooth / Q000187:drug effects; D010276:Parasympatholytics / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D014649:Vas Deferens / Q000187:drug effects
D008688:Methacholine Compounds; D018727:Muscarinic Antagonists; D010276:Parasympatholytics; D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; D006024:Glycopyrrolate