Development of a model for the delta-opioid receptor pharmacophore: 3. Comparison of the cyclic tetrapeptide, Tyr-c[D-Cys-Phe-D-Pen]OH with other conformationally constrained delta-receptor selective ligands

Biopolymers
A L LomizeH I Mosberg

Abstract

We have previously proposed a model of the delta-opioid receptor bound conformation for the cyclic tetrapeptide, Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13) based on its conformational analysis and from conformation-affinity relationships observed for its analogues with modified first and third residues. To further verify the model, it is compared here with results of conformational and structure-activity studies for other known conformationally constrained delta-selective ligands: the cyclic pentapeptide agonist, Tyr-c[D-Pen-Gly-Phe-D-Phe]OH (DPDPE): the peptide antagonist, Tyr-Tic-Phe-PheOH (TIPP); the alkaloid agonist, 7-spiroindanyloxymorphone (SIOM); and the related alkaloid antagonist, oxymorphindole (OMI). A candidate delta-bound conformer is identified for DPDPE that provides spatial overlap of the functionally important N-terminal NH3+ and C-terminal COO- groups and the aromatic rings of the Tyr and Phe residues in both cyclic peptides. It is shown that all delta-selective ligands considered have similar arrangements of their pharmacophoric elements, i.e., the tyramine moiety and a second aromatic ring (i.e., the rings of Phe3, Phe4, and Tic2 residues in JOM-13, DPDPE, and TIPP, respectively; the indole ring system in OMI, and t...Continue Reading

References

Jul 1, 1991·Biopolymers·G V NikiforovichC A Gehrig
Jun 1, 1990·Journal of Medicinal Chemistry·P S PortogheseA E Takemori
Oct 1, 1983·Proceedings of the National Academy of Sciences of the United States of America·H I MosbergT F Burks
Mar 4, 1994·Journal of Medicinal Chemistry·P S PortogheseA E Takemori

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