Conformationally constrained opioid ligands: the Dmt-Aba and Dmt-Aia versus Dmt-Tic scaffold.

Abstract

Replacement of the constrained phenylalanine analogue 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) in the opioid Dmt-Tic-Gly-NH-Bn scaffold by the 4-amino-1,2,4,5-tetrahydro-indolo[2,3-c]azepin-3-one (Aia) and 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) scaffolds has led to the discovery of novel potent mu-selective agonists (Structures 5 and 12) as well as potent and selective delta-opioid receptor antagonists (Structures 9 and 15). Both stereochemistry and N-terminal N,N-dimethylation proved to be crucial factors for opioid receptor selectivity and functional bioactivity in the investigated small peptidomimetic templates. In addition to the in vitro pharmacological evaluation, automated docking models of Dmt-Tic and Dmt-Aba analogues were constructed in order to rationalize the observed structure-activity data.

• Authors: Steven Ballet, Debby Feytens, Rien De Wachter, Magali De Vlaeminck, Ewa D Marczak, Severo Salvadori, Chris de Graaf, Didier Rognan, Lucia Negri, Roberta Lattanzi, Lawrence H Lazarus, Dirk Tourwé, Gianfranco Balboni
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 19 Issue 2 Pg. 433-7 (Jan 15 2009) ISSN: 1464-3405 [Electronic] England
• PMID: 19062273 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Ligands
• Receptors, Opioid, delta
• Receptors, Opioid, mu

Topics

• Ligands
• Methylation
• Models, Molecular
• Molecular Conformation
• Receptors, Opioid, delta (antagonists & inhibitors)
• Receptors, Opioid, mu (agonists)
• Stereoisomerism