5-Selective opioid agonist deltorphin

The peptides subtly modified in the side chain at N-terminus residue yielded an opioid with high dual affinities to both 8- and g-opioid receptor types. At present, it appears that the replacement of the Tyr residue by the innatural Dmt analogue in the 5- selective opioid agonist, deltorphin B, produced a peptide with high affinity for both g- and 8-opioid receptors, thereby yielding a 5-opioid receptor ligand which, to all intents and purposes, lacks 5-opioid receptor selectivity. 

When the efficacy of biphalin-stimulated G protein activation was examined (Table 3) in delta opioid receptor-transfected CHO cells, an efficacy ratio of 0.42 was determined as compared with deltorphin-II and DPDPE, the latter a reference delta-selective agonist. Such low efficacy values suggest that biphalin does not efficiently stimulate the G protein through the delta receptor [9]. Relative affinities of biphalin and morphine for mu, delta, and kappa binding sites in guinea pig brain membranes are shown in Table 4. 

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. 

Current evidence indicates that analgesia mediated by agonist activation of 8-opioid receptors [44] produces less marked side-effects than analgesia mediated by p-opioid receptors [18]. Deltorphins which represent the potent family of opioid peptides originally isolated from frog skin [45] are the most selective 8-opioid receptor peptides. Thus, they have served as parent peptide in the synthesis of numerous 8 active peptide analogues. 

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