Synthesis opioid peptides

In addition to the weU-defined opioid systems in the central nervous system, the three opioid peptides and their precursor mRNA have also been identified in peripheral tissues. ( -Endorphin is most abundant in the pituitary, where it exists in corticotroph cells with ACTH in the anterior lobe and in melanotroph cells with MSH in the intermediate lobe (59). Enkephalin and pre-pro-enkephalin mRNA have been identified in the adrenal medulla (60) and this has been the source of material for many studies of pro-enkephalin synthesis and regulation. Pre-pro-enkephalin mRNA has also been identified in the anterior and posterior lobes of the pituitary (61). mRNA for all three opioid precursors has been identified in the reproductive system (62—64). POMC... 

Ouyang, H., Vander Velde, D. G., Borchardt, R. T., Synthesis and conformational analysis of a coumarinic acid-based cyclic prodrag of an opioid peptide with modified sensitivity to esterase-catalyzed bioconversion. J. Peptide Res. 2002, 59, 183-195. 

KM Sivanandaiah, VV Suresh Babu, C Renukeshwar. Fmoc-amino acid chlorides in solid phase synthesis of opioid peptides. Int J Pept Prot Res 39, 201, 1992. 

Strategies for the design and synthesis of more stable opioid peptides... 

Ramakrishnan. K, and Portoghe.se, P. S., Synthesis and biological evaluation of a mcla/o-cine-containing cnkephalinamide. Evidence for nonidentical roles of the tyraminc moiety in opiates and opioid peptides. J. Med. Chem, 25, 142.3, 1982. 

Based on their finding amphibian skin peptides, which were counterparts to other mammalian bioactive peptides, Erspamer and coworkers examined amphibian skin for opioid peptides (see Ref 663 for a review). This led first to the isolation and characterization of dermorphin (212, Fig. 7.41), which is a ja-se-lective peptide (see Table 7.13), from the skin of South American Phyllemedusinae hylid frogs in the early 1980s (664). Inspection of the sequence of one of the cloned cDNAs for the precursor of dermorphin suggested the existence of another heptapeptide with a similar iV-terminal sequence (665). This then led to the isolation of deltorphin (alsocalled dermenkephalin or deltorphin A, 213, Fig. 7.41), the first S-selective amphibian opioid peptide, from these frogs (666, 667). Synthesis confirmed that the amino acid in position 2 of deltorphin was o-methionine rather than L-methionine (666,668, 669). Two additional peptides [o-Ala ldeltorphin I (also referred to as deltorphin C, 214, Fig. 7.41) and [o-Ala ]deltorphin II (also referred to as deltorphin B, 25, Fig. 7.5) were subsequently discovered (106) which exhibited even greater 8-receptor affinity and exceptional selectivity... 

Lu Y, Weltrowska G, Lemieux C et al (2001) Stereospecilic synthesis of (2S)-2-methyl-3-(2, 6 -dimethyl-4 -hydroxyphenyl)propionic acid (Mdp) and its incorporation into an opioid peptide. Bioorg Med Chem Lett 11 323-325... 

S. Udenfriend and J. Meienhofer, Eds., The Peptides Analysis, and Synthesis, Biology. Opioid Peptides Biology, Chemistry and Genetics, Vol. 6, Academic Press, New York, 19 4, pp 1-410. 

Sdentitic studies of opioid neurotransmitters during the 1970s have uncovered a complex and subtle system that exhibited impressive diversity in terms of endogenous ligands for only three major receptors. The opioid peptide precursors were subject to complex post-translational modifications resulting in the synthesis of multiple active peptides all of them sharing the common N-terminal sequence of Tyr-Gly-Gly-Phe-(Met or Leu), which has been termed the opioid motif. Based on the results of theses studies, the endogenous opioids have been implicated in circuits involved in the control of sensation, emotion, and affect and a role has been ascribed to them in addiction, not only to opiates such as morphine or heroin, but also to alcohol. ... 

Inhibition of estradiol-induced DNA synthesis by opioid peptides in the rat uterus Ordog, Tamas Vertes, Zsuzsanna Vertes, Marietta... 

Current evidence indicates that analgesia mediated by agonist activation of 8-opioid receptors [44] produces less marked side-effects than analgesia mediated by p-opioid receptors [18]. Deltorphins which represent the potent family of opioid peptides originally isolated from frog skin [45] are the most selective 8-opioid receptor peptides. Thus, they have served as parent peptide in the synthesis of numerous 8 active peptide analogues. 

Three distinct families of classical opioid peptides have been identified the enkephalins, endorphins, and dynorphins. Each family derives from a distinct precursor protein, prepro-opiome-lanocortin (POMC), preproenkephalin, and preprodynorphin, respectively, which are encoded by distinct genes. Each precursor is subject to complex cleavages and posttranslational modifications that result in the synthesis of multiple active peptides. The opioid peptides share a common amino-terminal sequence of Tyr-Gly-Gly-Phe-(Met or Leu), the opioid motif. This motif is followed by C-terminal extensions yielding peptides ranging from 5 to 31 residues (Table 21-1). 

A. Jakas and S. Horvat, Synthesis and NMR investigation of novel Amadori compounds (1-amino-1-deoxy-d-fructose derivatives) related to the opioid peptide, leucine-enkephalin, J. Chem. Soc. Perkin Trans. 2 (1996) 789-794. 

The enzyme works optimally at pH > 9 with N-protected amino acid esters as acyl donors, and amino acids or amino acid amides as nucleophiles (acceptors). At that pH value it has high esterase activity an amino acyl-enzyme complex will be formed rapidly which transfers the acyl residue to the acceptor molecule (transpeptidation), and since at alkaline pH the rate of peptide cleaving is minimal, the product formed will be released in excellent yield. As an example the last coupling step in a synthesis of the opioide peptide Met-enkephalin that started with benzoylarginine ethylester may be shown (Fig. 8). 

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