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

The phenolic group or the potent u and K opioid morphinan agonist/antagonists cyclorphan and butorphan was replaced by phenylamino and benzylamino groups including compounds with parasubstituents in the benzene ring. These compounds are highly potentp and K ligands, e,g., p-methoxyphenylaminocyclorphan showing a Ki of 0.026 nM at thep receptor and a Ki of 0.03 11M at tile K receptor. Phenyl carbamates and phenylureas were synthesized and investigated. Selective o-fomlylation of butorphan and levorphanol was achieved. This reaction opened the way to a large set of 2-SUbstitUtcd 3-hydroxymorphinans, including 2-hydroxyrilethyl-, 2-aminomethyl-, and N-substituted 2-aminomethyl-3-hydi-oxymoi-l)lmizms. Bivalent ligands bridged in the 2-position were also synthesized and connected with secondary and tertiary aminonlethyl 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.