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In an effort to develop antagonists for κ–μ opioid receptor heterodimers, a series of bivalent ligands 3–6 containing κ- and μ-antagonist pharmacophores were designed and synthesized. Evaluation of the series in HEK-293 cells revealed 4 (KMN-21) to selectively antagonize the activation of κ–μ heterodimers, suggesting possible bridging of receptors when the bivalent ligand spacer contains 21 atoms.
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