Deltorphin analogs

In related studies, Mosberget al. (230-232) carefully evaluated the cyclic truncated deltorphin analog H-Tyr-c-[D-Cys-Phe-D-Pen]-OH (JOM-13)in a series of structure-activity and conformational studies that used the j3-MePhe constraint (230) and alternative constraints for the position (see ref 231 for an excellent review). These studies led to the conclusion of the gauche (-) side-chain conformation for Xi in Phe and the trans side-chain conformation for the Tyr Xi (232). As expected the backbone conformations of... 

Miscika, A., Lipkowski, A. W., Horvath, R., Porreca, F., Yamamura, H. L, and Hmby, V. J. (1994) Delta-opioid receptor-selective ligands—DPLPE-deltorphin chimeric peptide analogs. Int. J. Pept. Protein Res. 44, 80-84. 

Linear Analogs. Among the naturally occurring deltorphins, [D-Ala ]deltorphin I... 

Amino acid substitution has provided information on the contributions of different residues in the deltorphin sequence to 6-receptor affinity and selectivity. A variety of substitutions have been made in each position of the deltorphins, resulting in hundreds of analogs reported in the literature. Only selected analogs and structural modifications are discussed here to illustrate key SAR for more detailed discussion readers are referred to recent detailed reviews (904,9051, which include extensive tables of analogs. 

The four isomers of j3-MePhe were incorporated into both [D-Ala ]deltorphin I and deltorphin (930). The peptides containing the 2jS isomers exhibit higher Breceptor affinity and agonist activity in the MVD than the analogs with the 2R isomers for both [D-Ala ]deltorphin I and deltorphin, consistent with the preference for l- over D-Phe in this position. The stereochemistry of the methyl group at the j3 position, however, had different effects on the 6 affinity and agonist... 

Early efforts to convert enkephalin into a selective 6-opioid ligand were successful in the development of c[D-Pen, D-Pen ]enkephalin (21 l)(DPDPE)and its analogs, which eventually led to analogs that were essentially specific for 8-opioid receptors as agonists, such as (2S,3i )j3-methyl-2, 6 -dimethyl tyrosine-c[D-Pen, u-Pen ]enkephalin (212, 213). The earlier aspects of this work have been thoroughly reviewed (214) and a selective update has recently appeared (215). A different kind of lead to 6-opioid ligands came from the discovery of the deltorphins (216, 217) such as H-Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH2 that are found in amphibian skins and have intrinsically highly delta opioid receptor selectivity. 

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