Development of a Peptide-derived orally-active kappa-opioid receptor agonist targeting peripheral pain.
Development of a Peptide-derived orally-active kappa-opioid receptor agonist targeting peripheral pain.
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DOI：
10.2174/1874104501307010016
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Dix TA
中科院分区：
文献类型：
--
作者：
Hughes FM Jr;Shaner BE;Brower JO;Woods RJ;Dix TA
κ-阿片样物质激动剂在治疗外周疼痛中特别有效，但遭受中枢神经系统（CNS）介导的作用，这限制了它们的发展。一种有前途的κ激动剂是肽化合物CR 665。虽然不能口服，但静脉注射CR 665表现出对CNS的高外周选择性，并使内脏和神经性疼痛患者受益。在这项研究中，我们已经产生了一系列的衍生物的CR 665和筛选他们的口服活性在醋酸诱导的大鼠扭体试验外周疼痛。进一步筛选了五种化合物的κ受体活化特异性以及μ和δ受体的激动和拮抗作用，这可能导致脱靶效应。所有活性衍生物都以低nM范围的EC 50与κ受体结合，而对κ的激动剂选择性超过μ或δ> 11，000 - 200，000倍。未检测到拮抗剂活性。选择一种化合物用于进一步分析（化合物9）。大鼠口服剂量反应9产生的EC 50为4.7 mg/kg，接近口服镇痛剂的可药用水平。为了评估该化合物的外周选择性，在扭体试验和热板试验（CNS介导的疼痛试验）中评估了大鼠的静脉给药反应。在扭体试验中的EC 50为0.032 mg/kg，而在热板试验中，在高达30 mg/kg的剂量下未检测到活性，表明外周选择性>900倍。我们建议，化合物9是一个候选人的发展作为一个口服可利用的外周限制性κ激动剂。
Kappa-opioid agonists are particularly efficacious in the treatment of peripheral pain but suffer from central nervous system (CNS)-mediated effects that limit their development. One promising kappa-agonist is the peptidic compound CR665. Although not orally available, CR665 given i.v. exhibits high peripheral to CNS selectivity and benefits patients with visceral and neuropathic pain. In this study we have generated a series of derivatives of CR665 and screened them for oral activity in the acetic acid-induced rat writhing assay for peripheral pain. Five compounds were further screened for specificity of activation of kappa receptors as well as agonism and antagonism at mu and delta receptors, which can lead to off-target effects. All active derivatives engaged the kappa receptor with EC50s in the low nM range while agonist selectivity for kappa over mu or delta was >11,000-200,000-fold. No antagonist activity was detected. One compound was chosen for further analysis (Compound 9). An oral dose response of 9 in rats yielded an EC50 of 4.7 mg/kg, approaching a druggable level for an oral analgesic. To assess the peripheral selectivity of this compound an i.v. dose response in rats was assessed in the writhing assay and hotplate assay (an assay of CNS-mediated pain). The EC50 in the writhing assay was 0.032 mg/kg while no activity was detectable in the hotplate assay at doses as high as 30 mg/kg, indicating a peripheral selectivity of >900-fold. We propose that compound 9 is a candidate for development as an orally-available peripherally-restricted kappa agonist.