Endorphins
Title: Endorphins
Literature References: Generic name derived from the term "endogenous morphine" and applied to a group of neuropeptides that are endogenous ligands of the opiate receptors. They are found in brain, pituitary gland and peripheral tissues of all vertebrates; the effects of endorphins on cells resemble those of opiates such as morphine. Their existence was postulated as a result of the discovery of stereospecific binding sites for narcotic analgesics in animal brain, cf. A. Goldstein et al., Proc. Natl. Acad. Sci. USA 68, 1742 (1971); C. B. Pert, S. H. Snyder, Science 179, 1011 (1973); E. J. Simon et al., Proc. Natl. Acad. Sci. USA 70, 1947 (1973). Three types of stereochemically related opiate receptors have been postulated, mu, delta, kappa: W. R. Martin et al., J. Pharmacol. Exp. Ther. 197, 517 (1976); P. E. Gilbert, W. R. Martin, ibid. 198, 66 (1976); J. A. H. Lord et al., Nature 267, 495 (1977). Of the endorphin group of peptides, several important members are known: a-, b- and g-endorphins (b-endorphin being the most potent), a-neo-endorphin, b-neo-endorphin, dynorphin, q.v., and met-enkephalin and leu-enkephalin, two naturally occurring pentapeptides belonging to the endorphin class. The amino acid sequences of a-, b- and g-endorphins are contained within the sequence 61-91 of b-lipotropin, and in each, the amino terminal pentapeptide sequence is that of met-enkephalin. Dynorphin and a- and b-neo-endorphins have common terminal leu-enkephalin sequences. Initial isoln of active oligopeptide: L. Terenius, A. Wahlstrom, Acta Pharmacol. Toxicol. 35, Suppl. 1, 55 (1974); J. Hughes, Brain Res. 88, 295 (1975). Isoln, characterization and synthesis of two active pentapeptides (enkephalins): J. Hughes et al., Life Sci. 16, 1753 (1975); G. W. Pasternak et al., ibid. 1765; J. Hughes et al., Nature 258, 577 (1975); J. D. Bower et al., J. Chem. Soc. Perkin Trans. 1 1976, 2488. Isoln and properties of b-endorphin from bovine pituitary: H. Teschemacher et al., Life Sci. 16, 1771 (1975); B. M. Cox et al., ibid. 1777. Identity of b-endorphin with carboxy terminal amino acid sequence (61-91) of b-lipotropin: C. H. Li, D. Chang, Proc. Natl. Acad. Sci. USA 73, 1145 (1976); B. M. Cox et al., ibid. 1821. Production of biologically active b-endorphin via expression of cloned gene sequences by E. coli: J. Shine et al., Nature 285, 456 (1980). For a review of isoln, amino acid sequences, and synthesis of b-endorphins from various species, see Hormonal Proteins and Peptides vol. X, entitled "b-Endorphin", C. H. Li, Ed. (Academic Press, New York, 1981) pp 2-30. Isoln and structure of a-endorphin or LPH (61-76): R. Guillemin et al., C.R. Seances Acad. Sci. Ser. D 282, 783 (1976); isoln, structure, synthesis of a- and g-endorphin or LPH (61-77): N. Ling et al., Proc. Natl. Acad. Sci. USA 73, 3942 (1976). High yield synthesis of met5-enkephalin: B. J. Dhotre et al., J. Indian Chem. Soc. 55, 1128 (1978). Rapid synthesis of leu5-enkephalin: E. Vilkas et al., Int. J. Pept. Protein Res. 15, 29 (1980). Isoln of a-neo-endorphin: K. Kagawa et al., Biochem. Biophys. Res. Commun. 86, 153 (1979). Amino acid sequence: eidem, ibid. 99, 871 (1981). Isoln, purification, amino acid sequence of b-neo-endorphin: N. Minamino et al., ibid. 864. Metabolism and physiological effects of endorphins: H. W. Kosterlitz, J. Hughes, Life Sci. 17, 91 (1975); L.-F. Tseng et al., Proc. Natl. Acad. Sci. USA 73, 4187 (1976). Although the physiological role of the endorphins has not been completely elucidated, they are known to block inhibitory pathways in the vertebrate CNS and their possible effects on pain perception, addictive states, and psychiatric disorders have been investigated: D. T. Krieger, A. S. Liotta, Science 205, 366 (1979); R. A. Nicoll et al., Nature 287, 22 (1980). Studies have also suggested that endorphins may be involved in gluco-regulation: M. Feldman et al., N. Engl. J. Med. 308, 350 (1983). Reviews: A. Goldstein, Science 193, 1081-1086 (1976); idem, Harvey Lect. 79, 291-314 (1979); R. A. North, Life Sci. 24, 1527-1546 (1979); C. R. Beddell et al., Prog. Med. Chem. 17, 1-39 (1980); several authors in Adv. Biochem. Pharmacol. 22, 145-642 (1980); M. S. Gold et al., Med. Res. Rev. 2, 211-246 (1982); S. Zakarian, D. G. Smyth, Biochem. J. 202, 561-571 (1982). Books: Opiates and Endogenous Opioid Peptides, H. W. Kosterlitz, Ed. (Elsevier, New York, 1976) 466 pp; Endorphins: Proceedings, L. Graf et al., Eds. (Elsevier, New York, 1979) 471 pp; Endorphins and Opiate Antagonists in Psychiatric Research, N. Shah, A. G. Donald, Eds. (Plenum, New York, 1982) 425 pp.
 
Derivative Type: b-Endorphin
Additional Names: b-Lipotropin C-fragment; b-lipotropin (61-91); LPH (61-91)
 
Derivative Type: Met5-Enkephalin
Additional Names: Methionine5-enkephalin; met5-E; L-tyrosylglycylglycyl-L-phenylalanyl-L-methionine; LPH (61-55)
Molecular Formula: C27H35N5O7S
Molecular Weight: 573.66
Percent Composition: C 56.53%, H 6.15%, N 12.21%, O 19.52%, S 5.59%
Properties: Needles from hot methanol, mp 196-198°. [a]22589 -21.9° (c = 1 in DMF); +14° (c = 1 in N HCl).
Melting point: mp 196-198°
Optical Rotation: [a]22589 -21.9° (c = 1 in DMF); +14° (c = 1 in N HCl)
 
Derivative Type: Leu5-Enkephalin
Additional Names: Leucine5-enkephalin; leu5-E; L-tyrosylglycylglycyl-L-phenylalanyl-L-leucine
Molecular Formula: C28H37N5O7
Molecular Weight: 555.62
Percent Composition: C 60.53%, H 6.71%, N 12.60%, O 20.16%
Properties: White crystalline solid, mp 206° (dec). [a]22589 -23.4° (c = 1 in DMF); +18.3° (c = 1 in N HCl).
Melting point: mp 206° (dec)
Optical Rotation: [a]22589 -23.4° (c = 1 in DMF); +18.3° (c = 1 in N HCl)

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