ANTIMUSCARINIC ACTION OF LIRIODENINE, ISOLATED FROM FISSISTIGMA-GLAUCESCENS, IN CANINE TRACHEAL SMOOTH-MUSCLE

1 The antimuscarinic properties of liriodenine, isolated from Fissisti gma glaucescens, were compared with methoctramine (cardioselective M(2 ) antagonist) and 4-diphenylacetoxy-N-methylpiperidine (4-DAMP, smooth muscle selective M(3) antagonist) by radioligand binding tests, funct ional tests and measurements of second messenger generation in canine cultured tracheal smooth muscle cells. 2 Liriodenine, pirenzepine, met hoctramine and 4-DAMP displaced [H-3]-N-methyl scopolamine ([H-3]-NMS) binding in a concentration-dependent manner with K-i values of 2.2 +/ - 0.4 x 10(-6), 3.3 +/- 0.7 x 10(-7), 8.9 +/- 2.3 x 10(-8) and 2.3 +/- 0.6 x 10(-9) M, respectively. The curves for competitive inhibition o f [H-3]-NMS with liriodenine, methoctramine and 4-DAMP were best fitte d according to a two site model of binding, but pirenzepine was best f itted according to a model with one site. 3 Liriodenine and 4-DAMP dis played a high affinity for blocking tracheal contraction (pK(B) = 5.9 and 9.1, respectively) and inositol phosphate formation (pK(B) = 6.0 a nd 8.9, respectively), but a low affinity for antagonism of cyclic AMP inhibition (pK(B) = 4.7 and 7.8, respectively). 4 Methoctramine block ed cyclic AMP inhibition with a high affinity (pK(B) = 7.4), but it an tagonized tracheal contraction and inositol phosphate formation with a low affinity (pK(B) = 6.1 and 6.0, respectively). 5 In conclusion, bo th M(2) and M(3) muscarinic receptor subtypes coexist in canine trache al smooth muscle and are coupled to the inhibition of cyclic AMP forma tion and phosphoinositide breakdown, respectively. The antimuscarinic characteristics of liriodenine are similar to those of 4-DAMP. It may act as a selective M(3) receptor antagonist in canine tracheal smooth muscle.