Univalent and Bivalent Ligands of Butorphan: Characteristics of the Linking Chain determine the Affinity and Potency of Such Opioid Ligands

摘要

Bivalent morphinan compounds containing ester linkers were synthesized and their binding affinities at the μ, δ, and κ opioid receptors determined. Addition of methyl groups adjacent to the hydrolytically labile ester linkage increased stability while only partially affecting binding affinity. The resulting bivalent ligands with optimized spacer-length and structure show potent binding profiles with the most potent compound (>4b) having Ki values of 0.47 nM for both the μ and κ opioid receptors, and >4a having Ki values of 0.95 and 0.62 nM for the μ and κ receptors, respectively. Both >4a and >4b were partial agonists at the κ and μ receptors in the [³⁵S]GTPγS binding assay.