Synthesis and binding affinity of novel mono- and bivalent morphinan ligands for κ, μ, and δ opioid receptors

• Published in: Bioorganic & medicinal chemistry 2011-05, Vol.19 (9), p.2808-2816
• Main Authors: Zhang, Bin, Zhang, Tangzhi, Sromek, Anna W., Scrimale, Thomas, Bidlack, Jean M., Neumeyer, John L.
• Format: Article
• Language: English
• Subjects: agonists; Animals; antagonists; binding capacity; Biological and medical sciences; Butorphan; Butorphanol; Butorphanol - chemistry; chemistry; CHO Cells; Cricetinae; Cricetulus; Decanoates - chemical synthesis; Decanoates - chemistry; Decanoates - pharmacology; Functional assays; Homo- and heterodimeric ligands; Humans; Kappa, delta and mu receptors; Ligands; Medical sciences; Morphinans; Morphinans - chemical synthesis; Morphinans - chemistry; Morphinans - pharmacology; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Opioids; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; pharmacology; Pharmacology. Drug treatments; Protein Binding; receptors; Receptors, Opioid, delta - chemistry; Receptors, Opioid, delta - metabolism; Receptors, Opioid, kappa - agonists; Receptors, Opioid, kappa - metabolism; Receptors, Opioid, mu - agonists; Receptors, Opioid, mu - antagonists & inhibitors; Receptors, Opioid, mu - metabolism
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2011.03.052

A novel series of homo- and heterodimeric ligands containing κ/μ agonist and μ agonist/antagonist pharmacophores joined by a 10-carbon ester linker chain were synthesized and evaluated for their in vitro binding affinity at κ, μ, and δ opioid receptors, and their functional activities were determined at κ and μ receptors in [ 35S]GTPγS functional assays. Most of these compounds had high binding affinity at μ and κ receptors ( K i values less than 1 nM). Compound 15b, which contains butorphan ( 1) at one end of linking chain and butorphanol ( 5) at the other end, was the most potent ligand in this series with binding affinity K i values of 0.089 nM at the μ receptor and 0.073 nM at the κ receptor. All of the morphinan-derived ligands were found to be partial κ and μ agonists; ATPM-derived ligands 12 and 11 were found to be full κ agonists and partial μ agonists.