Pharmacological characteristics of liriodenine, isolated from Fissistigma glaucescens, a novel muscarinic receptor antagonist in guinea-pigs

The pharmacological activities of liriodenine, isolated from Fissistigma glaucescens, were determined in isolated trachea, ileum and cardiac tissues of guinea-pigs. Liriodenine was found to be a muscarinic receptor antagonist in guinea-pig trachea as revealed by its competitive antagonism of carbachol (pA2 = 6.22 ± 0.08)-induced smooth muscle contraction. It was slightly more potent than methoctramine (pA2 = 5.92 ± 0.05), but was less potent than atropine (pA2 = 8.93 ± 0.07), pirenzepine (pA2= 7.02 ± 0.09) and 4-diphenylacetoxy-N-methylpiperidine (4-DAMP, pA2 = 8.72 ± 0.07). Liriodenine was also a muscarinic antagonist in guinea-pig ileum (pA2 = 6.36 ± 0.10) with a pA2 value that closely resembled that obtained in the trachea. Liriodenine was 10 fold less potent in atrial preparations (left atria, pA2 = 5.24 ± 0.04; right atria, pA2 = 5.35 ± 0.09 and 5.28 ± 0.07 for inotropic and chronotropic effects, respectively) than in smooth muscle preparations. High concentration of liriodenine (300 μM) partially depressed the contractions induced by U-46619, histamine, prostaglandin E(2α), neurokinin A, leukotriene C4 and high K+ in the guinea-pig trachea. The inhibitions were characterized by a rightward shift in the concentration-response curves with suppression of their maximal contraction. High concentration of liriodenine (300 μM) did not affect U-46619- or neurokinin A-induced tracheal contraction in the presence of nifedipine (1 μM) or in Ca2+-free (containing 0.2 mM EGTA) medium. Neither cyclic AMP nor cyclic GMP content of guinea-pig trachealis was changed by liriodenine (30-300 μM). It is concluded that liriodenine is a selective muscarinic receptor antagonist in isolated trachea, ileum and cardiac tissues of guinea-pigs. It is more potent in smooth muscle than in cardiac preparations. It also acts as a blocker of voltage-dependent Ca2+ channels at a high concentration (300 μM).