Dynorphin derivatives

Table 3.8. RECEPTOR BINDING AND SMOOTH MUSCLE ACTIVITY OF CYCLIC DYNORPHIN DERIVATIVES [95]...

The endogenous ligands for the opioid receptors are peptides known as the endorphins (endogenous morphine) or opio-peptins. These include the pentapep tides methionine-enkephalin and leucine-enkephalin and a hep tapep tide and octapeptide version of methionine-enkephalin, all derived from preproenkephalin p-endorphin derived from proopiomelanocortin a-and p-dynorphin derived from prodynorphin endomorphin-1 and -2, whose precursor has not been definitively identified and orphanin FQ or nociceptin, derived from OFQ/N precursor protein. These peptides are discussed in more detail in Chapter 34. 

Gomes, M.D. Juliano, L. Ferro, E.S. Matsueda, R. Camargo, A.C. (1993). Dynorphin-derived peptides reveal the presence of a critical cysteine for the activity of brain endo-oligopeptidase A. Biochem. Biophys. Res. Commun. Vol. 197(2), pp. 501-507. 

Biosynthesis. Three separate genes encode the opioid peptides (see Fig. 1). Enkephalin is derived from preproenkephalin A, which contains six copies of Met-enkephalin and extended peptides, and one copy of Leu-enkephalin (62—66). ( -Endorphin is one of the many products of POMC, and represents the N-terminal 31 amino acids of P-Hpotropin (67,68). Three different dynorphin peptides are derived from the third opioid gene, preproenkephalin B, or preprodynorphin (69). The dynorphin peptides include dynorphin A, dynorphin B, and a-neo-endorphin. 

The classic endogenous opioid peptides are derived from one of three families of precursors proopiomelanocortin (POMC), pro-dynorphin, and pro-enkephalin. Many active opioid peptides are derived from these three, but the best known are )S-endorphin, enkephalin, and dynorphin. POMC is produced by nuclei in the hypothalamus and medulla (Khachaturian et al. 1985 Watson et al. 1978 Bloom et al. 1978). Enkephalin and dynorphin neurons are distributed to all levels of the central nervous system (Hokfelt et al. 1977 Khachaturian et al. 1983 Sar et al. 1978 Khachaturian et al. 1985). 

Note Three distinct families of peptides have been identified the enkephalins, the endorphins, and the dynorphins. Each family is derived from a distinct precursor polypeptide and has a characteristic anatomical distribution. These precursors are now designated as proenkephalin (also proenkephalin A), proopiomelanocortin (POMP), and prodynorphin (also proenkephalin). 

Fentanyl and its derivatives are opioid narcotics similar to heroin and are consumed on the street in many of the same ways. These opioids work through receptors in the brain and spine, mimicking naturally present peptides commonly known as endorphins, enkephalins, and dynorphins. The type of receptor that fentanyl predominately bonds with is the mu receptor. 

Kuzmin, A., Madjid, N., Terenius, L., Ogren, S. O., and Bakalkin, G. (2006). Big dynorphin, a prodynorphin-derived peptide produces NMDA receptor-mediated effects on memory, anxiolyticlike and locomotor behavior in mice. Neuropychopharmacology 31, 1928-1937. 

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. 

Subsequently, numerous peptides with opioid-like effects have been found in the central nervous system and in peripheral tissues. These endogenous opioid peptides vary in size, but their amino terminals mostly share a similar enkephalin sequence of amino acids. Currently, four separate, individually gene-derived families of endogenous opioid peptides are recognized the endorphins, the enkephalins, the dynorphins and the endomorphins [17a], -Endorphin interacts predominantly with n and 6 receptors, Leu-enkephalin and Met-enkephalin interact predominantly with 5 receptors, dynorphin shows preference for k receptors [17b], while endomorphins 1 and 2 exhibit... 

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