Effects of Delphinium alkaloids on neuromuscular transmission

The Delphinium alkaloids methyllycaconitine (MLA), nudicauline, 14-deacetyl nudicauline (14-DN), barbinine, and deltaline were investigated for their e ffects on neuromuscular transmission in lizards. The substituent at C14 pro vides the only structural difference among the alkaloids MLA, nudicauline, 14-DN, and barbinine. Deltaline lacks the N-(methylsuccinyl)anthranilic aci d at C18 common to the other four alkaloids. Each alkaloid reversibly reduc ed extracellularly recorded compound muscle action potential (CMAP) amplitu des in a concentration-dependent manner. The IC50 values for CMAP blockade were between 0.32 and 13.2 mu M for the N-(methylsuccinimido)anthranoyllyca cotonine-type alkaloids and varied with the C14 moiety; the IC50 value for deltaline was 156 mu M. The slopes of the concentration-response curves for CMAP blockade were similar for each alkaloid except barbinine, whose shall ower curve suggested alternative or additional mechanisms of action. Each a lkaloid reversibly reduced intracellularly recorded spontaneous, miniature end-plate potential (MEPP) amplitudes. Alkaloid concentrations producing si milar reductions in MEPP amplitude were 0.05 mu M for 14-DN, 0.10 mu M for MLA, 0.50 mu M for barbinine, and 20 mu M for deltaline. Only barbinine alt ered the time constant for MEPP decay, further suggesting additional or alt ernative effects for this alkaloid. MLA and 14-DN blocked muscle contractio ns induced by exogenously added acetylcholine. All five alkaloids are likel y nicotinic receptor antagonists that reduce synaptic efficacy and block ne uromuscular transmission. The substituent at C14 determines the potency and possibly the mechanism of nicotinic acetylcholine receptor blockade for ML A, nudicauline, 14-DN, and barbinine at neuromuscular synapses. The lower p otency of deltaline indicates that the N-(methylsuccinyl)anthranilic acid a t C18 affects alkaloid interactions with nicotinic acetylcholine receptors at neuromuscular junctions.