"carba"-analogues of fentanyl are opioid receptor agonists

10.1021/jm9019068Journal of Medicinal Chemistry5372875-2881JMCM

Novel opioid peptide derived antagonists containing (2S)-2-methyl-3-(2,6- dimethyl-4-carbamoylphenyl)propanoic acid [(2S)-Mdcp]

10.1021/jm8004702Journal of Medicinal Chemistry51185866-5870JMCM

A Cyclic Tetrapeptide (“Cyclodal”) and Its Mirror-Image Isomer Are Both High-Affinity μ Opioid Receptor Antagonists

Head-to-tail cyclization of the μ opioid receptor (MOR) agonist [Dmt¹]­DALDA (H-Dmt-d-Arg-Phe-Lys-NH₂ (<b>9</b>; Dmt = 2′,6′-dimethyltyrosine) resulted in a highly active, selective MOR antagonist, c­[-d-Arg-Phe-Lys-Dmt-] (<b>1</b>) (“cyclodal”), with subnanomolar binding affinity. A docking study of cyclodal using the crystal structure of MOR in the inactive form showed a unique binding mode with the two basic residues of the ligand forming salt bridges with the Asp¹²⁷ and Glu²²⁹ receptor residues. Cyclodal showed high plasma stability and was able to cross the blood–brain barrier to reverse morphine-induced, centrally mediated analgesia when given intravenously. Surprisingly, the mirror-image isomer (optical antipode) of cyclodal, c­[-Arg-d-Phe-d-Lys-d-Dmt-] (<b>2</b>), also turned out to be a selective MOR antagonist with 1 nM binding affinity, and thus, these two compounds represent the first example of mirror image opioid receptor ligands with both optical antipodes having high binding affinity. Reduction of the Lys-Dmt peptide bond in cyclodal resulted in an analogue, c­[-d-Arg-Phe-LysΨ­[CH₂NH]­Dmt-] (<b>8</b>), with MOR agonist activity

A Cyclic Tetrapeptide (“Cyclodal”) and Its Mirror-Image Isomer Are Both High-Affinity μ Opioid Receptor Antagonists

Head-to-tail cyclization of the μ opioid receptor (MOR) agonist [Dmt¹]­DALDA (H-Dmt-d-Arg-Phe-Lys-NH₂ (<b>9</b>; Dmt = 2′,6′-dimethyltyrosine) resulted in a highly active, selective MOR antagonist, c­[-d-Arg-Phe-Lys-Dmt-] (<b>1</b>) (“cyclodal”), with subnanomolar binding affinity. A docking study of cyclodal using the crystal structure of MOR in the inactive form showed a unique binding mode with the two basic residues of the ligand forming salt bridges with the Asp¹²⁷ and Glu²²⁹ receptor residues. Cyclodal showed high plasma stability and was able to cross the blood–brain barrier to reverse morphine-induced, centrally mediated analgesia when given intravenously. Surprisingly, the mirror-image isomer (optical antipode) of cyclodal, c­[-Arg-d-Phe-d-Lys-d-Dmt-] (<b>2</b>), also turned out to be a selective MOR antagonist with 1 nM binding affinity, and thus, these two compounds represent the first example of mirror image opioid receptor ligands with both optical antipodes having high binding affinity. Reduction of the Lys-Dmt peptide bond in cyclodal resulted in an analogue, c­[-d-Arg-Phe-LysΨ­[CH₂NH]­Dmt-] (<b>8</b>), with MOR agonist activity