Deltorphin agonist activity

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... 

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. 

In summary, [Dmtr] deltorphin B possesses remarkable agonist activity and exerts effects on both g- and 8-opioid receptors in vitro and in vivo, and also that the newly discovered opioid tripeptide antagonist, DTA, exerts antagonist activity primarily toward the 8- opioid receptor, in keeping with in vitro data. 

In the RJ bioassay, 1-3 antagonized the potent 8d2-opioid receptor agonist deltorphin B with a pA2 ranging from 7.25 to 8.12. The agonist activity of 4 on GPI was due only to the interaction with p-receptors rather than k-receptors because 1-3 which are k-antagonists, failed to modify the IC50 of 4 in the same tissue (data not shown). 

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. 

Delta receptors nevertheless mediate some delta agonist induced analgesia, as suggested by reduced DPDPE and deltorphin activity in the DOR mutant after ITH applications [52], or enhanced antinociceptive activity in MOR mutants subjected to CFA inflammation [65]. Delta receptors also depress respiratory neurons in slice preparations [66] and mediate SNC80-evoked convulsions [67]. 

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... 

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],... 

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. 

Glycopeptide derivatives of the p-and 5-opioid receptor agonists deltorphin and dermorphin have been examined for in vivo activity [187,188]. Peptide agonists themselves generally only reach the central nervous system in low quantities, mainly due to their inability to cross the... 

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