ALPHA-CONOPEPTIDES: NOVEL RAPID-ACTING MUSCLE RELAXANTS

我们建议确定开发α-芋螺肽作为快速起效、持续时间短的肌肉松弛剂用于紧急情况下气管插管的可行性。α-芋螺肽GI和MI，最初从芋螺毒液中分离的二硫键桥接的小肽，是神经肌肉接头的烟碱受体的高度选择性竞争性拮抗剂。目前，琥珀酰胆碱是唯一的肌肉松弛剂，具有快速起效和短持续时间的必要特征，适用于在紧急情况下进行气管插管。不幸的是，琥珀酰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-芋螺肽GI抑制刺激诱导的大鼠胫骨前肌收缩，其起始和持续时间曲线与琥珀胆碱相似，因此可能是一种安全的替代方案。在第I阶段，我们将确定已知α-芋螺肽、通过分析来自新物种的cDNA文库鉴定的新型α-芋螺肽和嵌合α-芋螺肽在该动物模型中的效力、起效和持续时间以及副作用概况。在第II阶段，我们将在卵母细胞表达试验中表征成功的候选物，以更好地表征人神经肌肉烟碱受体两个界面的选择性;并表征猫和猪（一种与人类相当的大型动物）中的效价、起效时间、持续时间和副作用特征。拟议的商业应用：通过气管插管快速保护气道是必要的，以确保在紧急情况下充分通气，包括创伤，紧急剖宫产，重症监护室的危机，以及有呕吐和吸入风险的无意识患者。神经肌肉阻滞药物放松喉部肌肉，从而有助于气管插管。由于α-芋螺肽是高度特异性的神经肌肉阻滞药物，它们可能没有目前使用的肌肉松弛剂的副作用。因此，α-芋螺肽具有巨大的潜力，作为肌肉松弛药物，以促进气管插管。

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.