title: Design, synthesis, and biological evaluation of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4'-pyridyl)carboxamido]morphinan derivatives as peripheral selective μ opioid receptor Agents.
abstract: Peripheral selective μ opioid receptor (MOR) antagonists could alleviate the symptoms of opioid-induced constipation (OIC) without compromising the analgesic effect of opioids. However, a variety of adverse effects were associated with them, partially due to their relatively low MOR selectivity. NAP, a 6β-N-4'-pyridyl substituted naltrexamine derivative, was identified previously as a potent and highly selective MOR antagonist mainly acting within the peripheral nervous system. The noticeable diarrhea associated with it prompted the design and synthesis of its analogues in order to study its structure-activity relationship. Among them, compound 8 showed improved pharmacological profiles compared to the original lead, acting mainly at peripheral while increasing the intestinal motility in morphine-pelleted mice (ED(50) = 0.03 mg/kg). The slight decrease of the ED(50) compared to the original lead was well compensated by the unobserved adverse effect. Hence, this compound seems to be a more promising lead to develop novel therapeutic agents toward OIC.
authors.affiliation: Department of Medicinal Chemistry,  Virginia Commonwealth University , 800 East Leigh Street, Richmond, Virginia 23298, United States.
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Yuan
authors.forename: Orgil
authors.initials: O
authors.lastname: Elbegdorj
authors.forename: Jianyang
authors.initials: J
authors.lastname: Chen
authors.forename: Shashidhar K
authors.initials: SK
authors.lastname: Akubathini
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: David L
authors.initials: DL
authors.lastname: Stevens
authors.forename: Irina O
authors.initials: IO
authors.lastname: Beletskaya
authors.forename: Krista L
authors.initials: KL
authors.lastname: Scoggins
authors.forename: Zhenxian
authors.initials: Z
authors.lastname: Zhang
authors.forename: Phillip M
authors.initials: PM
authors.lastname: Gerk
authors.forename: Dana E
authors.initials: DE
authors.lastname: Selley
authors.forename: Hamid I
authors.initials: HI
authors.lastname: Akbarali
authors.forename: William L
authors.initials: WL
authors.lastname: Dewey
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D018938:Caco-2 Cells; D015195:Drug Design; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009019:Morphinans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D009022:Morphine Derivatives / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011869:Radioligand Assay; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: C577956:17-cyclopropylmethyl-3,14-dihydroxy-4,5-epoxy-6-((4'-(3'-methylpyridyl))carboxamido)morphinan; D000700:Analgesics; D009019:Morphinans; D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu