5-Agonist deltorphins

I.c.v. and i.t. administration of the 5 opioid agonist deltorphin II in rodents inhibits diarrhea and colonic bead expulsion in a dose-dependent manner but does not delay small intestine transit time. 5 agonists have been found to mediate mainly antisecretory effects and influence gut motility only marginally. These effects can be antagonized by pretreatment with NTI (Shook et al. 1989). 

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... 

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. 

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). 

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

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]. 

In addition to in vitro cell models, opioid agonists could induce the rapid endocytosis of the receptor in organo cultures or primary neuronal cultures, and also neurons in vivo. Treatment of longitudinal muscle-myenteric plexus preparation or the primary hippocampal neuron cultures with DAMGO resulted in internalization of the mu opioid receptor [146,147]. Similar observation was obtained with fluorescently labeled opioid peptides Fluo-dermorphin and Fluo-deltorphin [148]. Within 15 min of an intra-peritoneal injection of etorphine, mu opioid receptor immunoreactivity was observed in the endosomal structures of the myenteric neurons of guinea pig ileum [149]. Again, rapid clustering of a spliced variant of mu opioid receptor MOR-1C was observed in the lateral septum of the mouse after intracere-... 

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]. 

All the natural deltorphins, like the mu agonist dermorphins, contain the N-terminal sequence Tyr-D-Xaa-Phe, where the aromatic residues of Tyrl and Phe3 are of L configuration and the D-Xaa in the second position of the molecule is a D amino acid (D-Ala or D-Met or D-Leu). The D-enantiomer is encoded, however, by the codon for the L isomer in the precursor cDNA [8,13,15]. Thus, L-Xaa2 must be converted to D-Xaa2 by an unusual posttranslational reaction that presumably takes place in the precursor itself. 

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... 

Conversely, when injected ICV in rats, D-Ala-deltorphin-II was a weak partial agonist only doses >30 nmol produced some degree of antinocicep-... 

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. 

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