Characterization of the antimuscarinic effect of heptane-1,7-bis-(dimethyl-3'-phthalimidopropyl ammonium bromide).
The effect of heptane-1,7-bis-(dimethyl-3'-phthalimidopropyl ammonium bromide) (C7/3'-phthalimidopropyl), an alkane bisquaternary compound with muscarinic receptor blocking activity was studied in guinea-pig atria and ileal longitudinal muscle. C7/3'-phthalimidopropyl was a more potent inhibitor of atrial muscarinic receptors, the cardioselectivity being ca. 32-fold. Previous studies in guinea-pig atria have shown that its antimuscarinic effect was of an allosteric nature. In ileal longitudinal muscle C7/3'-phthalimidopropyl (3 to 100 microM) appeared to behave in a competitive manner towards carbachol but the combination of atropine or homatropine with C7/3'-phthalimidopropyl produced a supra-additive inhibitory effect on the responses to carbachol. In both atria and ileal longitudinal muscle homogenates, C7/3'-phthalimidopropyl also slowed the dissociation rate of [3H]QNB suggesting an allosteric mechanism. In binding studies using either [3H]QNB or [3H]oxo-M, C7/3'-phthalimidopropyl recognized two binding sites in atria and ileum. In both tissues, C7/3'-phthalimidopropyl bound with high affinity (ca. 30-70 nM) to 60-85% of the sites and with low affinity (ca. 1-9 microM) to the remaining sites. Correlation of these affinity constants with the dissociation constants obtained in functional studies in the two tissues is discussed.
Choo
L K
LK
School of Pharmacology, Victorian College of Pharmacy, Parkville, Australia.
Mitchelson
F
F
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D008725:Bis-Trimethylammonium Compounds / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D054833:Isoindoles; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D010276:Parasympatholytics / Q000494:pharmacology*; D011813:Quinuclidinyl Benzilate; D014326:Tropanes / Q000494:pharmacology
D008725:Bis-Trimethylammonium Compounds; D054833:Isoindoles; D010276:Parasympatholytics; D014326:Tropanes; C011268:heptane-1,7-bis(dimethyl-3'-phthalimidopropylammonium); D011813:Quinuclidinyl Benzilate; D001285:Atropine; C100236:homatropine