Opioid bifunctional ligands from morphine and the opioid pharmacophore Dmt-Tic

Bifunctional ligands containing an ester linkage between morphine and the δ-selective pharmacophore Dmt-Tic were synthesized, and their binding affinity and functional bioactivity at the μ, δ and κ opioid receptors determined. Bifunctional ligands containing or not a spacer of β-alanine between the two pharmacophores lose the μ agonism deriving from morphine becoming partial μ agonists 4 or μ antagonists 5. Partial κ agonism is evidenced only for compound 4. Finally, both compounds showed potent δ antagonism.

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► Morphine linked to the Dmt-Tic pharmacophore changes its pharmacological profile. μ Dmt-Tic-Morphine shows a  antagonist activity comparable to naloxone.
► Dmt-Tic maintains its  antagonist activity.