Delta receptors peptide

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 third prohormone from which opioid peptides are derived is pro-opiomelanocortin, which yields a number of nonopioid and opioid peptide products (O Donohue and Dorsa 1982). Of these products, beta-endorphin, an untriakontapeptide isolated from camel pituitary gland by Li and Chung (1976)) is thought to interact primarily with mu and delta receptors. 

The plant alkaloids mimic the endogenous peptides enkephalins and endorphins (Chapter 12), which meditate nociception and sleep. There are three types of widely distributed opiate receptors. Mu receptors are concentrated in neocortex, striatum, thalamus, hippocampus, amygdala and spinal cord, delta receptors in neocortex and amydala, and kappa receptors in striatum, amygdala and hypothalamus (Mansour et al., 1988). 

Vaught, J.L., Rothman, R.B., Westfall, T.C. Mu and delta receptors their role in analgesia in the differential effects of opioid peptides on analgesia, Life Sci. 1982, 30, 1443-1455. 

Delta receptor activation also produces analgesia, but it can also cause seizures as well. Delta receptors normally bind to a class of endogenous ligands known as enkephalins, but unlike mu receptors, information about delta receptors is limited. Enkephalins are peptides that are produced by the pituitary gland. Several different enkephalins have been identified. [3-Enkephalin resembles opiates because when it binds to a delta receptor, it relieves pain.11... 

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. 

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... 

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. 

Cloning of the opioid receptors did not come easy, and there were many false claims along the way. Efforts began in the mid-1980s in the wake of cloning of the opioid peptide precursors. However, it was not till 1992 that the delta receptor was first cloned and provided the critical probes leading to the characterization of the entire family of opioid receptors. 

Much attention focused on Trp284 joining EL3 and TM6 (Table 2). In the delta receptor, mutation of Trp284 into Lys affects peptide binding [25], mutation into Leu modifies affinity for the small alkaloid SNC80 [26], and mutation into Glu decreases naltrindole binding [15]. Interestingly, a marked... 

Synthetic peptides derived from the third intracellular loop of the delta receptor inhibit high-affinity binding of the delta peptide [3H] DSLET and G-protein activation by DSLET by competing with the activated receptor for recognition sites on Ga [11,12]. This is in agreement with studies on a variety of GPCRs that have demonstrated the third intracellular loop of the receptors to mediate much of the coupling between receptor and G protein [13,14]. 

Conformational analyses of JOM-13 and [L-Ala3]DPDPE have proven to be critical for the determination of the bioactive conformation of enkephalin-like peptides at the delta receptor. H-NMR studies of JOM-13 in aqueous solution revealed that this tetrapeptide exists in two distinct conformations on the NMR time scale as evidenced by two sets of resonances [63]. Large differences in the observed chemical shifts and coupling constants for the D-Cys2 residue in the two conformers suggested that the major differences between the two NMR conformers reside in the disulfide portion of the molecule however, a paucity of conformationally informative nuclear Overhauser enhancement (NOE) interactions precluded the development of a detailed structural model from the NMR studies. In order to develop such a model a thorough conformational analysis of JOM-13 was undertaken, in which the NMR data were complemented by x-ray diffraction results and by molecular mechanics calculations [64]. The results indicate that the 11-... 

To eliminate the remaining uncertainty regarding the bioactive conformations of DPDPE and JOM-13, the conformation of the Phe3,4 side chain, Phe in these peptides was replaced by (3-MePhe (all four isomers). The results [70,71] clearly suggested that both peptides bind to the delta receptor... 

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 NEP and APN levels are moderate on heart [74,75] while the concentration of both peptidases is higher in vascular endothelium or vagus nerve terminals [76-78]. However, the mechanisms and site of action (central or peripheral) involved in the cardioprotective effects of the endogenous opioid peptides remain unknown. Nevertheless, owing to their lack of narcotic effects, inhibition of endogenous enkephalin catabolism and subsequent stimulation of delta receptor could have interesting clinical applications in the cardiovascular domain. 

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-... 

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