Opioid Analgesics With Reduced Constipation

描述（由申请人提供）： 吗啡由于其对μ阿片受体的中枢作用而成为治疗严重疼痛的首选药物。通过重复给药，患者对镇痛作用变得耐受。对外周阿片受体的耐受性发展较慢，导致差异耐受和加重便秘效应。假设血脑屏障的外排转运蛋白在差异耐受性的发展中起作用。P-糖蛋白（P-gp）在吗啡耐受动物中表达上调，吗啡是P-gp的底物。因此，设计作为P-gp底物的活性降低的阿片类药物将导致镇痛剂减少便秘。假设去除4，5-环氧吗啡烷中的3-苯酚基团会降低P-gp亲和力，并且已知会降低对阿片受体的效力。高效的μ激动剂埃托啡与吗啡具有相似的P-gp底物亲和力。因此，替代埃托啡的3-苯酚将降低P-gp底物活性，并使阿片样物质的效力达到人体治疗水平。在20位的替换将改善所得弱P-gp底物的效力。长期目标是开发治疗慢性重度疼痛的新疗法。

DESCRIPTION (provided by applicant): Morphine is the drug of choice for the management of severe pain due to its central actions at mu opioid receptors. With repeated administration, patients become tolerant to the analgesic effects. Tolerance to peripheral opioid receptors develops more slowly, resulting in differential tolerance and an exacerbated constipatory effect. It is hypothesized that efflux transporters at the Blood-Brain Barrier play a role in the development of differential tolerance. P-glycoprotein (P-gp) is up regulated in morphine tolerant animals and morphine is a P-gp substrate. Therefore, the design of opioids with decreased activity as P-gp substrates will result in analgesics with reduced constipation. The removal of 3-phenol groups in 4,5-epoxymorphinans is hypothesized to decrease P-gp affinity and is known to reduce potency at opioid receptors. The highly potent mu agonist etorphine has similar P-gp substrate affinity to morphine. Replacement of the 3-phenol of etorphine will therefore reduce P-gp substrate activity and bring opioid potency to a therapeutic level in humans. Replacements at the 20-position will refine potency of the resulting weak P-gp substrates. The long-term goal is to develop novel therapeutics for the treatment of chronic, severe pain.