Deltorphins selectivity

The selectivity of currently used delta agonists may not be sufficient to avoid mu receptor activation in vivo. As an example, one study showed that DPDPE (selectivity delta/mu 100-fold) injected either ICV or ITH was less active in the mu receptor mutant than deltorphin (selectivity mu/delta 10,000-fold) [60]. This suggests that, in WT mice the less delta selective compound recruits mu receptors to produce analgesia in the tail flick and hot plate tests under their experimental conditions. 

Another class of 5-selective peptides, isolated from extracts of frog skin, is the deltorphins. These compounds are based on the stmcture... 

Selective agonists DAMGO DPDPE, D-ala2-deltorphin II Enadoline, U-50488 ... 

Erspamer Y, Melchiorri P, Falconieri-Erspamer G, et al. Deltorphins a family of naturally occurring peptides with high affinity and selectivity for opioid binding sites. Proc Natl Acad Sci USA 1989 86 5188-5192. 

Erspamer, V., Melchiorri, P., Falconieri-Erspamer, G., Negri, L., Corsi, R., Severin , C., Barra, D., Simmaco, M., Kreil, G. Deltorphins a family of naturally occurring peptides with high affinity and selectivity for Sopioid binding sites, Proc. Natl. Acad. Sci. USA 1989, 86, 5188-5192. 

The first peptide family of amphibian opiates was discovered in 1981 and named dermorphins [2,3], Until the discovery of mammalian endomor-phins by Zadina et al. [4], these peptides represented the most potent and selective mu opiate receptor agonists identified in living organisms. Nine years later, deltorphins were discovered in the amphibian skin. These peptides are still the most potent and selective delta opiate agonists available today [5]. 

Despite a common N-terminal tripeptide (Tyr-D-Xaa-Phe), the two groups of opioid peptides, dermorphins and deltorphins, differ enormously in receptor selectivities but bind to their own receptors with similar affinities. The N-terminal domain contains the minimum sequence essential for binding to opioid receptors whereas the C-terminal domain contains the address requisites for receptor selectivity. 

The N-terminal tetrapeptides of D-Met-deltorphin and D-Ala-deltor-phins did not show preference for delta receptors over mu receptors. The common determinants concurring to the remarkably efficient targeting of deltorphins towards the delta receptors were identified through structure-activity relationship studies conducted on an extensive series of synthetic analogues. The following structural requirements explain why the deltorphins are such potent and selective delta agonists a phenolic side chain (Tyr) and a... 

While D-Ala-deltorphins have delta-binding affinity similar to D-Met-deltorphin (0.3-2.0 nM), they consistently have the highest delta-opiate selectivity. The rank order of selectivity (Kih/Kip) is D-Ala-deltorphin-I = D-Ala-deltorphin-II (3000-4000) > D-Met-deltorphin (700) D-Ile-deltor-phin (100) D-Leu-deltorphin heptadecapeptide or its N-terminal deca-peptide fragment. 

The high delta-selectivity of D-Ala-deltorphins can be attributed to their C-terminal tetrapeptide sequence in which the anionic residue plays an important role. Elimination of the charge at the fourth position normally results in opiates that have similar delta and mu affinity and generally lack selectivity. Substitution of Gly in the fourth position would permit D-Ala-... 

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. 

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