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Abstract: Colubrid snake venoms potentially represent a vast source of novel biological actives and structural motifs owing to their diverse phylogeny. The present study describes the identification of rufoxin, a neurotoxin from the venom of Rhamphiophis oxyrhynchus (Rufous beaked snake) which is a member of the African colubrid lineage, the psammophiines. Rufoxin (1μM) displayed reversible post-synaptic neurotoxic activity as evidenced by significant inhibition of indirect twitches and responses to exogenous nicotinic agonists in the chick biventer cervicis nerve–muscle preparation. Rufoxin (0.1–1.0μM) also caused a rightward parallel shift of cumulative concentration–response curves to carbachol (CCh; 0.6–80μM) without a significant depression of the maximum response, suggestive of classical competitive antagonism at the skeletal muscle nicotinic receptor. Rufoxin lacks NH2-terminal sequence homology to previously identified snake venom toxins. This work indicates a wider distribution of neurotoxins across the advanced snake superfamily than previously described. [Copyright &y& Elsevier]

Abstract: In this study, we have pharmacologically characterised boigatoxin-A, a three finger toxin isolated from the venom of the colubrid, Boiga dendrophila (Mangrove catsnake). In the chick biventer cervicis nerve-muscle preparation boigatoxin-A (1μM) displayed poorly reversible postsynaptic blockade as evidenced by the inhibition of indirect (0.1Hz, 0.2ms, supramaximal V) twitches and responses to exogenous acetylcholine (1mM) and carbachol (20μM). Boigatoxin-A (0.3–0.5μM) caused a concentration-dependent depression of the maximum response of cumulative concentration response curves to CCh (0.6–80μM). Boigatoxin-A (1μM) induced readily reversible inhibition of electrically evoked (0.2Hz, 0.3ms, 70–100V) twitches of the prostatic segment of the rat vas deferens. This inhibition was not significantly attenuated by 8-phenyltheophylline (20μM) or idazoxan (1μM). Boigatoxin-A (1μM) did not affect α,β-mATP (10μM) or noradrenaline (25μM) responses in unstimulated epididymal segments of the rat vas deferens. Our data suggests that this toxin has weak postsynaptic neurotoxicity in skeletal muscle and also prejunctional neurotoxic activity in the smooth muscle of the rat vas deferens to inhibit the release of neurotransmitter(s), but not via prejunctional purinergic or adrenergic receptors. This is the first report of such activity for a toxin isolated from snake venom and reinforces the largely untapped potential of colubrid venoms. [Copyright &y& Elsevier]

Abstract: The venom of R. oxyrhynchus, a member of the psammophiine subfamily of the colubrid assemblage, was examined for biological activity using biochemical and pharmacological techniques. Venom displayed a high protein content, a complex electrophorectic profile and PLA2 activity but no detectable proteolytic or haematological activities. In the chick biventer cervicis nerve muscle preparation, venom (1–10μg/ml) displayed postsynaptic neurotoxic activity as evidenced by inhibition of indirect (0.1Hz, 0.2ms, supramaximal V) twitches and responses to exogenous acetylcholine (1mM) and carbachol (20μM). This inhibitory effect was poorly reversible by washing. Venom (30–50μg/ml) caused a rapid and readily reversible inhibition of direct (0.1Hz, 2ms, supramaximal V) twitches of the chick biventer cervicis nerve muscle preparation without morphological changes to the muscle fibers. Venom (30–100μg/ml) inhibited electrically-evoked (0.2Hz, 0.3ms, 70–100V) twitches of the prostatic segment of the rat vas deferens. This inhibitory effect was not significantly attenuated by 8-phenyltheophylline (8-PT; 20μM), idazoxan (1μM), a combination of ranitidine (0.2μM) and thioperamide (10μM) or capsazepine (10μM). Venom (5mg/kg) induced hypotension with subsequent cardiovascular collapse in the anaesthetised rat. The cardiovascular collapse was prevented by artificial respiration of the animals prior to venom administration. The biological activities demonstrated by R. oxyrhynchus venom may aid in prey envenomation strategies such as prey immobilisation. This study provides further evidence that colubrid venoms are comprised of multiple components which can display a variety of actions, some of which may be novel, therefore reinforcing the largely untapped potential of colubrid venoms. [Copyright &y& Elsevier]

In this study, venoms from species in the Colubrinae, Homalopsinae, Natricinae, Pseudoxyrhophiinae and Psammophiinae snake families were assayed for activity in the chick biventer cervicis skeletal nerve muscle preparation. Boiga dendrophila, Boiga cynodon, Boiga dendrophila gemincincta, Boiga drapiezii, Boiga irregularis, Boiga nigriceps and Telescopus dhara venoms (10 μg/ml) displayed postsynaptic neuromuscular activity as evidenced by inhibition of indirect (0.1 Hz, 0.2 ms, supramaximal V) twitches. Neostigmine (5 μM) reversed the inhibition caused by B. cynodon venom (10 μg/ml) while the inhibitory effects of Psammophis mossambicus venom (10 μg/ml) spontaneously reversed, indicating a reversible mode of action for both venoms. Trimorphodon biscutatus (10 μg/ml) displayed irreversible presynaptic neurotoxic activity. Detectable levels of phospholipase A2 activity were found only in T. biscutatus, T. dhara and P. mossambicus venoms. The results demonstrate a hitherto unsuspected diversity of pharmacological actions in all lineages which may have implications ranging from clinical management of envenomings to venom evolution. [Copyright &y& Elsevier]

Abstract: A number of ω-conotoxin GVIA mimetics based on an anthranilamide core were prepared and tested for their affinity for rat brain Cav2.2 channels. Features such as the presence of hydroxyl and fluoro substituents on the tyrosine side chain mimic, the length of the chains on the lysine/arginine side chain mimics and the use of diguanidino and diamino substituents rather than mono-guanidine/mono-amine substitution were examined. The diguanidinylated compounds proved to be the most active and deletion of the hydroxyl substituent had a limited influence on activity. The SAR associated with variation in the lysine/arginine side chain mimics was not strong. The introduction of a fluoro substituent into the tyrosine mimic produced the most active compound prepared in this study (2g), with an EC50 at rat brain Cav2.2 channels of 6μM. [Copyright &y& Elsevier]

We report the discovery of conopressin-T, a novel bioactive peptide isolated from Conus tulipa venom. Conopressin-T belongs to the vasopressin-like peptide family and displays high sequence homology to the mammalian hormone oxytocin (OT) and to vasotocin, the endogenous vasopressin analogue found in teleost fish, the cone snail's prey. Conopressin-T was found to act as a selective antagonist at the human V1a receptor. All peptides in this family contain two conserved amino acids within the exocyclic tripeptide (Pro7 and Gly9), which are replaced with Leu7 and Val9 in conopressin-T. Whereas conopressin-T binds only to OT and V1a receptors, an L7P analogue had increased affinity for the V1a receptor and weak V2 receptor binding. Surprisingly, replacing Gly9 with Val9 in OT and vasopressin revealed that this position can function as an agonist/antagonist switch at the V1a receptor. NMR structures of both conopressin-T and L7P analogue revealed a marked difference in the orientation of the exocyclic tripeptide that may serve as templates for the design of novel ligands with enhanced affinity for the V1a receptor. [ABSTRACT FROM AUTHOR]

Abstract: We report the synthesis and biological activity of a low molecular weight non-peptidic mimic of the analgesic peptide ω-conotoxin GVIA. The molecular weight of this compound presents a reduction by 193g/mol compared to a previously reported lead. This compound exhibits an EC50 of 5.8μM and is accessible in only six synthetic steps compared to the original lead (13 steps). We also report several improvements to the original synthetic route. [Copyright &y& Elsevier]