Opioid Analgesics With Reduced Constipation

减少便秘的阿片类镇痛药

• 批准号: 7284109
• 负责人: CHRISTOPHER W CUNNINGHAM
• 金额: $ 2.65万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7284109
• 关键词: Absence of pain sensation; Acquired Immunodeficiency Syndrome; Affect; Affinity; Agonist; Alkanes; Amides; Amines; Analgesics; Animals; Biological Assay; Blood - brain barrier anatomy; Charcoal; Chronic; Clinic; Codeine; Constipation; Data; Development; Dose; Esters; Ethers; Ethyl Ether; Etorphine; Excision; Fellowship; Goals; Human; In Vitro; Individual; Lead; Life; Methyl Ethers; Morphine; Mus; Names; Opioid; Opioid Analgesics; Opioid Receptor; P-Glycoprotein; P-Glycoproteins; Pain; Parents; Patients; Peripheral; Pharmaceutical Preparations; Phenols; Play; Positioning Attribute; Range; Rate; Rattus; Role; Skeleton; Structure-Activity Relationship; Therapeutic; Transcriptional Activation; Up-Regulation; analog; brain tract; cancer surgery; chronic pain; desensitization; design; desire; in vivo; mu opioid receptors; novel therapeutics; receptor

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.

描述（由申请人提供）： 吗啡因其对 mu 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，导致耐受性差异和便秘效应加剧。据推测，血脑屏障的外排转运蛋白在差异耐受性的发展中发挥作用。 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 底物将产生减少便秘的镇痛药。假设去除 4,5-环氧吗啡喃中的 3-酚基团会降低 P-gp 亲和力，并且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，替代埃托啡的 3-苯酚将降低 P-gp 底物活性，并使阿片类药物的效力达到人类的治疗水平。 20 位的替换将提高所得弱 P-gp 底物的效力。长期目标是开发治疗慢性严重疼痛的新疗法。