MUSCARINIC TOXINS FROM THE VENOM OF DENDROASPIS SNAKES WITH AGONIST-LIKE ACTIONS

The venom of some Dendroaspis snakes contains small proteins (7500 mol . wt) that inhibit the binding of radiolabelled muscarinic antagonist to brain synaptomal membranes. There were no peptides described among muscarinic ligands until Adem et al. (Biochim. biophys. Acta 968, 340- 345, 1988) reported that muscarinic toxins (MTxs), MTx1 and 2 were abl e to inhibit H-3-QNB binding to rat brain membranes. Since MTxs inhibi t around half of specific binding of H-3-quinuclidinyl benzilate (H-3- QNB) and H-3-N-methyl-scopolamine (H-3-NMS), which do not discriminate between subtypes of muscarinic receptors, it has been proposed that M Txs might selectively bind to some subtype. MTx1 and 2 from Dendroaspi s angusticeps almost completely inhibit the binding of H-3-pirenzepine (H-3-PZ), a preferential M(1) muscarinic receptor subtype ligand to c erebral cortex synaptosomal membranes. A much higher concentration was needed to inhibit partially H-3-PZ binding to atrial muscarinic recep tors. These results support the hypothesis that MTx1 and 2 may be M(1) selective muscarinic ligands. Similar activities have been found in D endroaspis polylepis and D. viridis venoms, but with lower affinities. The K-i obtained from inhibition curves of the binding of H-3-PZ show ed that MTx1 has higher affinity for the putative M(1) muscarinic rece ptor subtype, followed by MTx2. DpMTx has lower affinity, while DvMTx seems to have the lowest affinity. All these peptides are devoid of an ticholinesterase activity. Dendrotoxin and fasciculin from D. angustic eps venom do not inhibit the binding of muscarinic radioligands to cer ebral cortex membranes. The injection of MTxs into dorsal hippocampus of rats immediately after training in an inhibitory avoidance task imp roves memory consolidation, as does oxotremorine. This improvement is antagonized by the joint administration of the muscarinic antagonist s copolamine. These results suggest that MTxs behave as a muscarinic ago nist, at least in this case. Therefore, the muscarinic toxins from ela pid snakes may be useful tools since they are proteins that might be s elective muscarinic ligands, that seem to be agonists in the case of M Txs from D. angusticeps venom.