14‐Membered cyclic opioids related to dermorphin and their partially retro‐inverso modified analogues

Abstract

As a continuation of our program to study structure‐activity relationships of opiate peptides, we report the syntheses and biological activities of a series of 14‐membered cyclic dermorphin analogues closely related to enkephalin analogue Tyr‐c[d‐A2bu‐Gly‐Phe‐Leu] incorporating a phenylalanine at the third position in place of glycine. In addition to two parent dermorphin analogues Tyr‐c[d‐A2bu‐Phe‐Phe‐(l and D)‐Leu], four stereoisomeric retro‐inverso modified analogues Tyr‐c[D‐A2bu‐Phe‐gPhe‐(S and R)‐mLeu] with a reversed amide bond between residues four and five, and Tyr‐c[d‐Glu‐Phe‐gPhe‐(L and D)‐rLeu] with two reversed amide bonds between residues four and five, and between residue five and the side chain of residue two have been synthesized. The results from the guinea pig ileum (GPI) and mouse vas deferens (MVD) assays show that all analogues are superactive at either one or both opiate receptors and in general display higher activities as compared to the corresponding enkephalin analogues with a glycine at the third position. Results from the in vitro biological assays and conformational analysis using 1H‐NMR spectroscopy (adjoining paper) will provide useful information to understand the role of the Phe3 aromatic side chain in dermorphin, and that of the Phe4 aromatic side chain in enkephalin, on opiate activity since these cyclic dermorphin analogues contain two Phe residues at both the third and fourth positions.

Peptide and protein mimetics by retro and retroinverso analogs

“…The retro analog of HSP (heat shock protein) folds properly as well as form a tetramer same as the original HSP which is a 12.6 kDa protein (Shukla, Raje, & Guptasarma, 2003). Retroinverso analogs of opiate peptides also mimic the biological function of the opiate peptides (Said-Nejad et al, 1992). A mini retroinverso antibody also has been synthesized which binds to the same peptide as the original antibody (Levi, Hinkula, & Wahren, 2000).…”

14‐Membered cyclic opioids related to dermorphin and their partially retro‐inverso modified analogues II. Preferred conformations in solution as studied by 1H‐NMR spectroscopy

“…2, together with the vicinal coupling constant values given in Tables 1 and 2. For HDh of the L-and D-Leu residues, NOEs from Hfih to the NH of the same residues and large values of Jz.ph (10.54 Hz for the 14-Membered cyclic dermorphin analogues For the gPhe residue, the gPhe NH refers to the NH originally present in the Phe residue as opposed to the gPhe N *H which is formed during the synthesis of the gem-diaminoalkane moiety (15). For the mLeu residue, the mLeu C* is adjacent to the gPhe residue while the mLeu CO is adjacent to the D-AZbu side chain.…”

“…The two protons of the CHz groups and the two &methyl groups of the mLeu residucs are distinguishcd by appending a superscript h for the one in the higher field and 1 for that in the lower field. For the gPhe residue, the gPhe N H refers to the NH originally present in the Phe residue as opposed to the gPhe N * H formed during the synthesis of the gem-diaminoalkane moiety (15). protons in the 14-membered ring, a small value of 0.2 ppb Kwas obtained for the exocyclic ring D-G~u NH proton, suggesting that this amide proton is involved in an intramolecular hydrogen bond ( Table 9).…”

“…The two protons of the CHZ groups and the two &-methyl groups of the mLeu residues are distinguished by appending a superscript h for the one in the higher field and I for that m the lower field. For the gPhe N H refers to the N H originally present in the Phe residue as opposed to the gPhe N * H formed during the synthesis of the gern-diaminoalkane moiety(15).…”

Interaction Energy Analysis of Peptide can Predict the Possibilities of Mimetics by its Retroinverso Isomer

“…The mimetics of an RI isomer of peptides and proteins holds promise for medical and industrial applications such as making protease resistant analogs of therapeutic peptides and synthesizing chiral isomers of enzymatic reaction products using corresponding R enzymes. Partial RI analogs have also been explored as an alternative where the complete RI analog did not work (10–13). Guptasarma (6) has hypothesized a geometrical transformation to understand the relationship between the structure of a peptide and its RI analog.…”