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, 19 (2), 433-7

Conformationally Constrained Opioid Ligands: The Dmt-Aba and Dmt-Aia Versus Dmt-Tic Scaffold

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Conformationally Constrained Opioid Ligands: The Dmt-Aba and Dmt-Aia Versus Dmt-Tic Scaffold

Steven Ballet et al. Bioorg Med Chem Lett.

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.

Figures

Figure 1
Figure 1
Structures of the Dmt-Tic 1, Dmt-Aba 2 and Dmt-Aia 3 scaffolds
Figure 2
Figure 2
Reference compounds Dmt-Tic-NH-Bn 4 and Dmt-Aba-Gly-NH-Bn 5.
Figure 3
Figure 3
Docking poses of: (A) JOM13 (green carbon atoms) and (B) compound 4 (yellow carbon atoms) in the DOR receptor model. The backbone of transmembrane helices 5, 6, and 7 are represented by magenta ribbons (TM3 is not shown for clarity). Important binding residues are depicted as ball-and-sticks with grey carbon atoms. Oxygen, nitrogen, sulphur and hydrogen atoms are coloured red, blue, orange and cyan, respectively. H-bonds described in the text are depicted by white dots.
Figure 4
Figure 4
Docking poses of: (A) JOM6 (green carbon atoms) and (B) compound 5 (yellow carbon atoms) in the MOR receptor model. Rendering and colour coding are the same as defined for Fig. 3.
Figure 5
Figure 5
Superposition of the docking poses of compound 5 (blue) and compound 10 (red) in the MOR receptor model.

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