Of deltorphin

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... 

TABLE 2 Inhibitory Potencies of Deltorphins and Some Analogues on Electrically Evoked Contractions of Mouse Vas Deferens (MVD) and Guinea Pig Ileum (GPI), and on the Specific Binding of 0.3 nM [3H]D-Ala-Deltorphin-I and of 0.5 nM [3H]DAGO at Delta and Mu Sites in Rat Brain Membranes... 

Table 3 ICV Doses of Deltorphins Inducing Behavioral Effects...

Further pharmacological effects of deltorphins have been demonstrated under various experimental conditions. D-Ala-deltorphin improves memory consolidation in a passive avoidance apparatus in mice this effect is abolished by naltrindole [75]. D-Ala-deltorphin-II caused hypothermia in cold-adapted animals [76]. In contrast to mu opiate agonists, D-Ala-deltorphin-I, at low doses, stimulates respiratory activity in fetal lambs, and this effect is blocked by simultaneous administration of naltrindole [77], The peptide D-Ala-deltorphin-II inhibits diarrhea induced by castor oil and colonic bead expulsion, but it leaves the rate of transit through the small intestine unchanged [78,79]. By the SC route D-Ala-deltorphin-I inhibits acidified alcohol-induced gastric mucosal lesions [80], but by the ICV route, it fails to affect gastric secretion [81], The peptide is involved also in the control of ingestive behavior. It stimulates the intake of food [82] and of sucrose [83],... 

Based on their finding amphibian skin peptides, which were counterparts to other mammalian bioactive peptides, Erspamer and coworkers examined amphibian skin for opioid peptides (see Ref 663 for a review). This led first to the isolation and characterization of dermorphin (212, Fig. 7.41), which is a ja-se-lective peptide (see Table 7.13), from the skin of South American Phyllemedusinae hylid frogs in the early 1980s (664). Inspection of the sequence of one of the cloned cDNAs for the precursor of dermorphin suggested the existence of another heptapeptide with a similar iV-terminal sequence (665). This then led to the isolation of deltorphin (alsocalled dermenkephalin or deltorphin A, 213, Fig. 7.41), the first S-selective amphibian opioid peptide, from these frogs (666, 667). Synthesis confirmed that the amino acid in position 2 of deltorphin was o-methionine rather than L-methionine (666,668, 669). Two additional peptides [o-Ala ldeltorphin I (also referred to as deltorphin C, 214, Fig. 7.41) and [o-Ala ]deltorphin II (also referred to as deltorphin B, 25, Fig. 7.5) were subsequently discovered (106) which exhibited even greater 8-receptor affinity and exceptional selectivity... 

Opioid Receptor Affinities and Opioid Activity in the GPI and MVD of Deltorphin... 

The C-terminal truncation of the deltorphins can affect both receptor affinity and selectivity. Demnidation of both [o-Ala ldeltorphin I and II causes significant decreases in receptor affinity (25- to 50-fold) and 6 selectivity (908, 914, 915). Although there is one report of a large (90-fold) decrease in 6-receptor affinity upon conversion of deltorphin to the C-termi-nal acid (914), there are other reports that deamidation of this heptapeptide causes only a small decrease (916), or even a slight increase... 

The N-terminal tetrapeptide amide fragment of [o-Ala ] deltorphin I (T3n--D-Ala-Phe-AspNHg) shows a slight preference for fx receptors (908,915), but its affinity (K = 100-195 nM) and selectivity for fx receptors is much lower compared to that of the iV-termi-nal tetrapeptide amide fragment of deltorphin [Tyr-D-Met-Phe-HisNHg (fx) = 8.0 nM],... 

Amino acid substitutions in the C-terminus of deltorphin have also focused mainly on the charged residues His and Asp. As was found for Asp /Glu in [o-Ala ] deltorphin I and II, His appears to play an important role in the... 

On conformational point of view the activity of the analogues including DMT in deltorphin B can be explained on the basis of a conformation of the N-terminal portion of deltorphin B where the rotation of the Tyr residue is sensibly reduced. 

Role of D-glucopyranosyl moiety in the pharmacological activity of Deltorphin C and dermorphin. 

---