Incorporation of a novel conformationally restricted tyrosine analog into a cyclic, .delta. opioid receptor selective tetrapeptide (JOM-13) enhances .delta. receptor binding affinity and selectivity

Journal of Medicinal Chemistry
1992.0

Abstract

The incorporation of conformational constraints in biologically active peptide analogs is a well-established approach for enhancing receptor selectivity. In the opioid peptide area, previous bicyclic tyrosine/phenylalanine analogs limit both χ1 (dihedral angle about the Cα-Cβ bond) and χ2 (dihedral angle about the Cβ-Cγ bond), which hinders interpretation of their roles in binding affinity. We report a novel conformationally restricted tyrosine analog, trans-3-(4'-hydroxyphenyl)proline (t-Hpp), which curtails orientational freedom about χ1 but allows unrestricted rotation about χ2. Incorporating t-Hpp into the cyclic δ opioid receptor selective tetrapeptide JOM-13 (Tyr-c[D-Cys-Phe-D-Pen]OH) yielded diastereomeric analogs 2 and 3. Binding assays using guinea pig brain homogenates showed analog 2 (tentatively assigned as the L-t-Hpp1 analog) had similar μ receptor affinity but approximately 3-fold enhanced δ receptor affinity compared with JOM-13, resulting in ~3-fold higher δ selectivity. Compared with the δ selectivity reference DPDPE, analog 2 exhibited comparable δ selectivity and 6-fold higher δ affinity. Replacement of Tyr1 in JOM-13 with NMeTyr1 (mimicking the secondary amine of t-Hpp) had no significant effect on binding, indicating the high affinity of 2 is driven by conformational restriction rather than the imino acid nature of t-Hpp. This confirms the Tyr1 residue in JOM-13 adopts χ1 between ~-85° and ~-150° in both solution (supported by NMR) and δ receptor binding. Our results suggest t-Hpp is a valuable conformationally restricted tyrosine analog for bioactive peptides, aiding in elucidating tyrosine side-chain orientations in bioactive conformations.

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