ALPHA-CONOPEPTIDES: NOVEL RAPID-ACTING MUSCLE RELAXANTS

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We propose to determine the feasibility of developing alpha- conopeptides as rapidly acting, short duration muscle relaxants for facilitating tracheal intubation in emergency situations. Alpha- Conopeptides GI and MI, small disulphide-bridged peptides originally isolated from cone snail venom, are highly selective competitive antagonists of nicotinic receptors of the neuromuscular junction. Currently, succinylcholine is the only muscle relaxant with the requisite profile of rapid onset and short duration suitable for facilitating tracheal intubation in emergency situations. Unfortunately, succinylcholine is limited by side effects including cardiovascular complications and malignant hyperthermia. Preliminary data indicate that alpha-conopeptide GI inhibits stimulation-induced contraction of the rat tibialis anterior muscle with an onset and duration profile similar to succinylcholine, and therefore may represent a safe alternative. In phase I we will determine the potency, onset and duration, and side effect profiles of known alpha- conopeptides, novel alpha-conopeptides identified by analysis of cDNA libraries from new species, and chimeric alpha-conopeptides in this animal model. In phase II we will characterize successful candidates in oocyte expression assays to better characterize the selectivity at the two interfaces of the human neuromuscular nicotinic receptor; and characterize the potency, onset, duration and side effect profile in felines and swine (a larger animal comparable to humans). PROPOSED COMMERCIAL APPLICATIONS: Rapid protection of the airway by tracheal intubation is necessary to ensure adequate ventilation in emergency situations including trauma, emergency cesarean section, crises in intensive care, and unconscious patients at risk for vomiting and aspiration. Neuromuscular blocking drugs relax the muscles of the larynx thereby facilitating tracheal intubation. Since alpha-conopeptides are highly specific neuromuscular blocking drugs they may lack the side effects of currently used muscle relaxants. Thus, alpha-conopeptides have tremendous potential as muscle relaxing drugs for facilitating tracheal intubation.