ALPHA-CONOPEPTIDES: NOVEL RAPID-ACTING MUSCLE RELAXANTS

我们建议确定开发α-柯罗多肽作为快速、短效肌肉松弛药的可行性，以便在紧急情况下促进气管插管。α-二硫代肽GI和MI是最初从锥螺毒液中分离出来的二硫键小分子多肽，是神经肌肉接头烟碱受体的高度选择性竞争性拮抗剂。目前，琥珀酰胆碱是唯一一种起效快、持续时间短的肌松剂，适用于紧急情况下的气管插管。不幸的是，琥珀胆碱受到副作用的限制，包括心血管并发症和恶性高热。初步数据表明，α-刀豆肽GI抑制刺激诱导的大鼠胫前肌收缩，其起效和持续时间与琥珀胆碱相似，因此可能是一种安全的替代药物。在第一阶段，我们将在这个动物模型中确定已知的α-螺杆菌多肽、通过分析新物种的cDNA文库鉴定的新的α-螺杆菌多肽以及嵌合的α-螺杆菌多肽的效力、起效和持续时间以及副作用分布。在第二阶段，我们将鉴定成功的候选卵子表达分析，以更好地表征人类神经肌肉尼古丁受体两个界面的选择性；并表征猫和猪(与人类相似的较大动物)的效力、起效、持续时间和副作用。建议的商业应用：通过气管插管快速保护呼吸道是必要的，以确保在紧急情况下有足够的通风，包括创伤、紧急剖腹产、重症监护危象以及有呕吐和吸入风险的昏迷患者。神经肌肉阻滞剂松弛喉部肌肉，从而促进气管插管。由于α-螺杆菌多肽是高度特异的神经肌肉阻滞剂，它们可能没有目前使用的肌肉松弛药的副作用。因此，α-刀豆肽作为促进气管插管的肌肉松弛药物具有巨大的潜力。

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.