Design, Synthesis, and Biological Evaluation of the Third Generation 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4'-pyridyl)carboxamido]morphinan (NAP) Derivatives as μ/κ Opioid Receptor Dual Selective Ligands.

Analgesics, Opioid / pharmacology Animals Binding Sites Constipation / chemically induced Drug Design Ligands Male Mice Molecular Conformation Molecular Docking Simulation Morphinans / chemistry Morphine / pharmacology Receptors, Opioid, kappa / antagonists & inhibitors Receptors, Opioid, mu / antagonists & inhibitors Structure-Activity Relationship

Journal

Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531

Informations de publication

Date de publication:
24 01 2019
Historique:
pubmed: 5 1 2019
medline: 29 10 2019
entrez: 5 1 2019
Statut: ppublish

Résumé

μ opioid receptor (MOR) agonists have been widely applied for treating moderate to severe pain. However, numerous adverse effects have been associated with their application, including opioid-induced constipation (OIC), respiratory depression, and addiction. On the basis of previous work in our laboratory, NAP, a 6β- N-4'-pyridyl substituted naltrexamine derivative, was identified as a peripheral MOR antagonist that may be used to treat OIC. To further explore its structure-activity relationship, a new series of NAP derivatives were designed, synthesized, and biologically evaluated. Among these derivatives, NFP and NYP significantly antagonized the antinociception effect of morphine. Whereas NAP acted mainly peripherally, its derivatives NFP and NYP actually can act centrally. Furthermore, NFP produced significantly lesser withdrawal symptoms than naloxone at similar doses. These results suggest that NFP has the potential to be a lead compound to treat opioid abuse and addiction.

Identifiants

DOI: 10.1021/acs.jmedchem.8b01158 PMID: 30608693 PMC: PMC6467700
pubmed: 30608693
doi: 10.1021/acs.jmedchem.8b01158
pmc: PMC6467700
mid: NIHMS1006603
doi:

Substances chimiques

Analgesics, Opioid 0
Ligands 0
Morphinans 0
Receptors, Opioid, kappa 0
Receptors, Opioid, mu 0
Morphine 76I7G6D29C

Types de publication

Journal Article Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

561-574

Subventions

Organisme : NIDA NIH HHS
ID : R01 DA024022
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA044855
Pays : United States

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Auteurs

Yi Zheng (Y)

Department of Medicinal Chemistry , Virginia Commonwealth University , 800 E. Leigh Street , Richmond , Virginia 23298 , United States.

Samuel Obeng (S)

Department of Medicinal Chemistry , Virginia Commonwealth University , 800 E. Leigh Street , Richmond , Virginia 23298 , United States.

Huiqun Wang (H)

Department of Medicinal Chemistry , Virginia Commonwealth University , 800 E. Leigh Street , Richmond , Virginia 23298 , United States.

Abdulmajeed M Jali (AM)

Department of Pharmacology and Toxicology , Virginia Commonwealth University , 1112 East Clay Street , Richmond , Virginia 23298 , United States.

Bharath Peddibhotla (B)

Department of Medicinal Chemistry , Virginia Commonwealth University , 800 E. Leigh Street , Richmond , Virginia 23298 , United States.

Dwight A Williams (DA)

Department of Medicinal Chemistry , Virginia Commonwealth University , 800 E. Leigh Street , Richmond , Virginia 23298 , United States.

Chuanchun Zou (C)

Department of Medicinal Chemistry , Virginia Commonwealth University , 800 E. Leigh Street , Richmond , Virginia 23298 , United States.

David L Stevens (DL)

Department of Pharmacology and Toxicology , Virginia Commonwealth University , 1112 East Clay Street , Richmond , Virginia 23298 , United States.

William L Dewey (WL)

Department of Pharmacology and Toxicology , Virginia Commonwealth University , 1112 East Clay Street , Richmond , Virginia 23298 , United States.

Hamid I Akbarali (HI)

Department of Pharmacology and Toxicology , Virginia Commonwealth University , 1112 East Clay Street , Richmond , Virginia 23298 , United States.

Dana E Selley (DE)

Department of Pharmacology and Toxicology , Virginia Commonwealth University , 1112 East Clay Street , Richmond , Virginia 23298 , United States.

Yan Zhang (Y)

Department of Medicinal Chemistry , Virginia Commonwealth University , 800 E. Leigh Street , Richmond , Virginia 23298 , United States.
ORCID: 0000-0001-8934-7016

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Classifications MeSH

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