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

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.