Enkephalins biological activity

The Group III peptides come from the 256-amino acid precursor, pro-dynorphin [88402-55-5] (pro-enkephalin B). This group contains dynorphin A [80448-90-4] and B [85006-82-2] as weU as a-neoendorphin [77739-20-9] (Fig. 2), all of which can be further cleaved to form biologically active iatermediates, eg, dynorphin A g and P-neoendorphin [77739-21-0] (a-neoendorphin ) (28). The longer of these peptides are relatively basic because of the number of Lys and Arg residues. 

The spin-spin coupling constants [2-4] of the enkephalins in solution can be interpreted in terms of folded conformations resembling that of morphine in the placement of the residues which appear important for biological activity. X-ray crystallography and theoretical calculations (4-9) have also shown that methionine and leucine enkephalin adopt conformations similar to those concluded from NMR studies. Hence it would appear that opioid peptides can topographically resemble the opiates by assuming preferred, folded, conformations. However, earlier studies from this laboratory (TO) have shown that NMR data can be interpreted in terms of a conformationally flexible structure for methionine enkephalin. 

Some of the peptides mentioned are overlapping in the POMC sequence. For example, additional cleavage of ACTH gives rise to a-MSH and corticotropin-like intermediary peptide (CLIP). Proteolytic degradation of p-LPH provides y-LPH and p-endorphin. The latter can be further broken down to yield met-enkephalin, while y-LPH can still give rise to p-MSH (not shown). Due to the numerous derivative products with biological activity that it has, POMC is also known as a polyprotein. Which end product is formed and in what amounts depends on the activity of the proteinases in the ER that catalyze the individual cleavages. 

After the early discovery of a tyrosine 0-sulfate residue in bovine fibrinopeptide B, 15 this posttranslational modification which occurs ubiquitously in proteins was also detected in a series of biologically active peptides such as the neurohormones of the gastrin/cholecysto-kinin (CCK) family of peptides, phyllokinin, Leu-enkephalin, and the thrombin inhibitor hirudin listed in Table 1. 

Researchers have reasoned that if the water-soluble peptide leu-enkephalin could be conjugated with an oxidizable hydrophobic chain, and further shielded with a hydrophobic domain provided by cholesterol via an ester linkage, the modihed leu-enkephalin could become sufficiently hydrophobic to breach the blood-brain barrier. The oxidation of one of the engineered domains in the brain would produce an ionic form that cannot redistribute back into blood, and is essentially locked in. The ester linkages could then be hydrolyzed by esterases in brain tissues to release biologically active leu-enkephalin (Figure 13.12). 

Compounds 32 and 33 (Scheme 13), reported in the 1980s,1t79,80 were designed as mimetics of the pentapeptide Met-enkephalin. Both compounds had very poor biological activity, which could be attributable to a number of features. 

Huffman et alJ161 have also incorporated a /ram-alkene y-turn mimetic into a series of enkephalin analogues 14 (Scheme 9) with complete loss of biological activity and into an HIV-1 protease inhibitor replacing the -Asn-Tyr-Pro- sequence in 15 corresponding to the P2-Pi-P( positions of the peptide substrate giving 16[39-401 (Scheme 10). 

The endorphins are a group of naturally occurring neuroproteins that act in a manner similar to morphine to control pain. Research has shown that the biologically active part of the endorphin molecule is a simple pentapeptide called an enkephalin, with the structure Tyr-Gly-Gly-Phe-Met. Draw the complete structure of this enkephalin. 

We have also prepared a propargylic acid derivative of the pentapeptide enkephalin (see below), which was reacted, after cleavage and purification, with Co2(CO)g in solution to yield the Co2(CO)6(alkyne) derivative [31]. Similarly, other Co2(CO)6 alkynyl peptides were synthesized from the preprepared peptide and Co2(CO)g in solution (see Sect. 2.2.2 and the section below on biological activity) [32]. In a related fashion, the Co2(CO)6 moiety can also be introduced C-terminally (see Sect. 2.2.3) or internally (see Sect. 2.2.2). 

The utility of this method was demonstrated in the synthesis of a biologically active pentapeptide leucin enkephalin (45) where Boc-protected 45 (46) could be removed from the resin in 88% yield (56% after purification).70... 

Fig. 2) (9-11). Alternatively, a precursor may contain multiple related copies of the active neuropeptide. For example, proenkephalin contains four copies of (Met)enkephalin, one copy of the related (Leu)enkephalin, and one copy each of the ME-Arg-Gly-Leu and ME-Arg-Phe (Fig. 2) (12-14). Proteolysis of these precursors, especially tissue-specific proteolytic mechanisms, is required for biologically active neuropeptides to be generated. 

---