Delta-receptor-selective peptide

Both DADLE and DPDPE together with some other delta-receptor-selective peptides have been employed extensively and intensively for canying out numerous in vitro studies initially. Based on... 

Although above mentioned delta and mu receptor selective peptides and opiates were observed and useful for the identification of distinctive delta receptor from other opioid receptors, they suffered from the low selectivity and cross-actions at high doses or concentrations of these ligands, especially in in vivo pharmacological studies. The needs of having highly selective ligands for all types of opioid receptors were clear. In addition to the above... 

Delta receptors are relatively selective for two related penta-peptides, methionine enkephalin and leucine enkephalin (met- and leu-enkephalin), which were isolated from porcine brain (Hughes 1975). Both met- and leu-enkephalin inhibit electrically induced contractions of guinea pig ileum, an effect that mimics those effects seen with opioid drugs, and is naloxone reversible. The enkephalins are processed posttranslational ly from proenkephalin, and secreted from central and peripheral neurons and endocrine cells in the adrenal medulla. 

The endogenous opioid peptides have a range of affinities for the different types of opioid receptor. Some met-enkephalin derivatives, for example, show affinity for mu and delta receptors, whereas other peptides, derived from proenkephalin, show a preference for the delta sites. All peptides from prodynorphin act predominantly on kappa sites, while beta-endorphin behaves like the enkephalins and shows selectivity for the mu and delta sites. 

Prodynorphin contains three copies of Leu-enkephalin with carboxy-termi-nus extended polypeptides of various lengths known as dynorphin A (or dynorphin 1-17), dynorphin B (dynorphin 1-13), or a- and 3-neoendorphin. These peptides derived from prodynorphin are selective to kappa receptors and can also be further broken down to Leu-enkephalin. The identification of the delta receptor (or the enkephalin receptor) was a direct consequence of the discovery of enkephalins. This chapter will review the major events that are important for the identification of delta receptors and the subsequent cloning of delta receptor genes, and eventually all other opioid receptor genes. 

DISCOVERY OF DELTA AND MU RECEPTOR HIGHLY SELECTIVE PEPTIDE ANALOGS... 

In 1984, Cotton and colleagues described ICI174,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH) as a highly selective antagonist for the delta receptors [34]. This peptide was later discovered by Hertz and colleagues [35,36] to be the first inverse delta agonist. 

The structures of selected peptide and nonpeptide delta-selective opioid antagonists are shown in Figure 1. However, although the compounds shown in Figure 1 have been introduced as neutral delta opioid antagonists, data from more sensitive functional assay systems have subsequently proven that these compounds are also capable of behaving as inverse agonists at the delta opioid receptor under appropriate conditions. 

In its compact crystal structure, the two opioid tetrapeptide pharmacophores of biphalin are not conformationally equivalent. One tetrapeptide, which has a steric similarity with the delta-selective peptide DADLE, folds into a random coil. The contralateral tetrapeptide, sterically similar to the mu-selective peptide D-TIPP-NH2, exhibits a fairly normal type III (3 bend [4]- These conformational features suggest that under physiological conditions, biphalin may easily bind to these respective opioid receptors. This duality of binding affinity is probably the reason that biphalin is able to interact with all opioid receptor types. 

The ability of delta opioid receptors to modulate pain perception in mice is illustrated by the antinociceptive activity of a number of delta-selective peptides as well as nonpeptide alkaloids [27,28]. Delta opioid receptor-... 

SNC80 (( +)-4-[(aR)-a-((2S,5R)-4-allyl-2,5-dimethyl-l-piperazinyl)-3-methoxy-benzyl]-N,N-diethylbenzamide), the O-methylated derivative of ( + )-BW373U86,has an affinity of 1 nMfor delta opioid receptors. Moreover, SNC80 has more than 500-fold selectivity for delta versus mu opioid receptors, which is much greater than the receptor selectivity of the parent compound BW373U86 and similar to that of the most selective peptidic delta opioid receptor agonists [40-42]. SNC80 produces weak but replicable antinociceptive effects. 

The direct effects opioid and opioidlike peptides exhibit on cells of the immune system is both varied and, in some instances, contradictory, depending on which receptor subtype is being studied. Mu and kappa receptors generally affect immunofunction in a suppressive manner, where delta receptors tend to express immunostimulation [82-85]. However, selected delta antagonists have shown to elicit suppressive effects on B-cell proliferation, NK cell activity, and T-helper cell cytokine production [86]. The alteration of leukocyte function via opioid receptors will be discussed highlighting specific cell subtype immunomodulation. Endorphin shows a inhibitory effect on splenocyte proliferation through central and peripheral autocrine/paracrine pathways [87]. 

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