C14-aminosteroid LNF 209, an agent with positive inotropic and antimuscarinic activity.
LNF 209 is a cardioactive steroid containing at position C14 a protonized amino group. It was tested whether LNF 209 has antimuscarinic properties besides its cardiotonic effect, which was also quantified. In guinea pig left atria (3 Hz, 0.9 mM Ca2+, 5.4 mM K+), LNF 209 increased the force of contraction at concentrations > or = 1 microM, thus having a tenfold lower potency than ouabain. Correspondingly, cardiac glycoside binding sites in guinea pig cardiac membranes labeled with [3H]ouabain were occupied by LNF 209 (Ki = 1.7 microM) at concentrations tenfold higher compared with ouabain (Kd = 0.14 microM). The negative inotropic effect of the muscarinic agonist oxotremorine was antagonized by LNF 209, but not by ouabain; in the Schild plot, the data for LNF 209 could be connected by a line with a slope of unity and a pA2 = 7.5. The binding of [3H]N-methylscopolamine ([3H]NMS) to the M2-cholinoceptors in guinea pig cardiac membranes was inhibited by LNF 209 with a Ki = 0.5 microM; LNF reduced the affinity of [3H]NMS binding without affecting the number of receptor sites. In isolated segments of guinea pig ileum, LNF 209 antagonized the effect of oxotremorine with a pA2 = 7.4. It is concluded that LNF 209 is a competitive antagonist at M-cholinoceptors without preference for the cardiac M2-cholinoceptors. Whether the antimuscarinic property is of significance in species highly sensitive to digitalis remains to be established.
D000731:Androstanes / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D002316:Cardiotonic Agents / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008362:Mannosides / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D019832:N-Methylscopolamine; D010042:Ouabain / Q000378:metabolism; D010095:Oxotremorine / Q000037:antagonists & inhibitors; D010276:Parasympatholytics / Q000494:pharmacology*; D011869:Radioligand Assay; D011976:Receptors, Muscarinic / Q000187:drug effects*; D012602:Scopolamine Derivatives / Q000378:metabolism; D013268:Stimulation, Chemical
D000731:Androstanes; D002316:Cardiotonic Agents; D008362:Mannosides; D010276:Parasympatholytics; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; C078453:LNF 209; D010042:Ouabain; D010095:Oxotremorine; D019832:N-Methylscopolamine