Opioid Analgesics With Reduced Constipation

描述(由申请人提供)： 吗啡是治疗剧烈疼痛的首选药物，因为它对u阿片受体起中枢作用。通过反复给药，患者对止痛效果变得耐受。对外周阿片受体的耐受性发展较慢，导致差异耐受性和加重便秘效应。假设血脑屏障的外流转运体在差异耐受的形成中起作用。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，设计活性降低的阿片类药物作为P-gp底物将导致止痛药减少便秘。4，5-环氧吗啡中3-苯酚基团的去除被认为会降低P-gp亲和力，并已知会降低阿片受体的效力。高效MU激动剂埃托啡与吗啡具有相似的P-gp底物亲和力。因此，取代依托啡的3-苯酚将降低P-gp底物的活性，并将阿片类药物的效力提高到治疗水平。在20位的替换将提高所产生的弱P-gp底物的效力。长期目标是开发治疗慢性剧烈疼痛的新疗法。

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.