Synthesis and Opioid Receptor Binding Affinities of 2-Substituted and 3-Aminomorphinans: Ligands for μ, κ, and δ Opioid Receptors

• Published in: Journal of medicinal chemistry Vol. 53; no. 1; pp. 402 - 418
• Main Authors: Decker, Michael, Si, Yu-Gui, Knapp, Brian I, Bidlack, Jean M, Neumeyer, John L
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.01.2010; Amer Chemical Soc
• Subjects: Binding Sites; Chemistry, Medicinal; Life Sciences & Biomedicine; Ligands; Molecular Conformation; Morphinans - chemical synthesis; Morphinans - chemistry; Morphinans - pharmacology; Narcotic Antagonists; Pharmacology & Pharmacy; Science & Technology; Structure-Activity Relationship; COCAINE; ANALOGS; DERIVATIVES; BIVALENT LIGANDS; MORPHINAN; PALLADIUM-CATALYZED AMINATION
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9013482

The phenolic group of the potent μ and κ opioid morphinan agonist/antagonists cyclorphan and butorphan was replaced by phenylamino and benzylamino groups including compounds with para-substituents in the benzene ring. These compounds are highly potent μ and κ ligands, e.g., p-methoxyphenylaminocyclorphan showing a K i of 0.026 nM at the μ receptor and a K i of 0.03 nM at the κ receptor. Phenyl carbamates and phenylureas were synthesized and investigated. Selective o-formylation of butorphan and levorphanol was achieved. This reaction opened the way to a large set of 2-substituted 3-hydroxymorphinans, including 2-hydroxymethyl-, 2-aminomethyl-, and N-substituted 2-aminomethyl-3-hydroxymorphinans. Bivalent ligands bridged in the 2-position were also synthesized and connected with secondary and tertiary aminomethyl groups, amide bonds, and hydroxymethylene groups, respectively. Although most of the 2-substituted morphinans showed considerably lower affinities compared to their parent compounds, the bivalent ligand approach led to significantly higher affinities compared to the univalent 2-substituted morphinans.