Comparative analysis of various proposed models of the receptor-bound conformation of H-Tyr-Tic-Phe-OH related delta-opioid antagonists

Biopolymers
Brian C Wilkes, P W Schiller

Abstract

A molecular mechanics study (grid search and energy minimization) was performed with six delta opioid peptide antagonists containing a tetrahydroisoquinoline-3-carboxylic acid (Tic) residue in the 2-position of the peptide sequence. Compounds examined were the highly potent and selective TIP(P) peptides H-Tyr-Tic-Phe-OH (TIP), H-Tyr-Tic psi[CH2-NH]Phe-OH (TIP[psi]), H-Tyr-Tic-Phe-Phe-OH (TIPP), and H-Tyr-Tic psi[CH2-NH]Phe-Phe-OH (TIPP[psi]), and the weakly active analogues H-Tyr-Tic-NH2 and H-Tyr-Tic-Ala-OH. Low energy conformers of the peptides were examined for their compatibility with three proposed models of the delta receptor-bound conformation. Model 1, based on spatial overlap of the Tyr1 and Phe3 aromatic rings and N-terminal amino group of the peptides with the corresponding aromatic rings and nitrogen atom of the nonpeptide delta-antagonist naltrindole, was ruled out because of the demonstrated importance of the Tic2 aromatic ring for delta antagonism and because of the somewhat elevated energies of the conformers consistent with this model. Models of the receptor-bound conformation based on superimposition of the Tyr1 and Tic2 aromatic rings and N-terminal amino group of the peptides with the corresponding moieties ...Continue Reading

References

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Citations

Jan 23, 2003·Biopolymers·Jeffrey R DeschampsClifford George
Apr 29, 1998·Trends in Pharmacological Sciences·S D BryantL H Lazarus
Oct 16, 2009·Journal of Medicinal Chemistry·Irena BerezowskaPeter W Schiller
Dec 9, 2008·Bioorganic & Medicinal Chemistry Letters·Steven BalletGianfranco Balboni
Mar 14, 2007·Bioorganic & Medicinal Chemistry Letters·Roland E DolleRobert N DeHaven
Jun 5, 2004·Bioorganic & Medicinal Chemistry Letters·Roland E DolleRobert N DeHaven
Mar 11, 1999·Journal of Receptor and Signal Transduction Research·P W SchillerB C Wilkes
May 1, 1997·The Journal of Peptide Research : Official Journal of the American Peptide Society·J L Flippen-AndersonG Nikiforovich
May 30, 1998·The Journal of Peptide Research : Official Journal of the American Peptide Society·B C WilkesP W Schiller
Jan 1, 1997·Journal of Peptide Science : an Official Publication of the European Peptide Society·R SchwyzerH U Gremlich
Feb 20, 2009·The Journal of Organic Chemistry·Irina DenissovaYvan Guindon
Sep 5, 2003·Journal of Medicinal Chemistry·Johannes SchützHelmut Schmidhammer
Nov 24, 2005·Journal of Medicinal Chemistry·Denzil BernardAlexander D MacKerell Jr

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