Peptides, opioid

Akil et al, (1984) observed that the endogenous opioid peptides are invariably synthesized as essential component associated with the structures of specific large precursor proteins. Evidently, each of the major types of opioid peptides does have an altogether different and specific precursor protein. 

Salient Features. The various salient features of the opioid peptides are stated as under  

In 1975 a discovery of major importance was reported by J. Hughes, H.W. Kosterlitz and associates [36]. They found, in the brain, two closely related pentapeptides with potent opiate activity. The enkephalins. 

The opioid peptides stem from a large precursor molecule in which several copies of the enkephalins are present, the ratio between Met-enkephalin and Leu-enkephalin being 6 1 [39]. The same precursor, pro-opiocortin, also contains a modified form of the enkephalin sequence in which the N-terminal tyrosine is present as the sulfate ester [40]. This kind of post-translational change has been discussed in connection with gastrin, cholecystokinin and caerulein (p. 165). The last mentioned peptide prompts us to recall dermorphin (p. 186), an opioid peptide found in the skin of an amphibian. 

Although the pain-killing properties of morphine and related compounds have been known for a considerable time (see page 329), the existence of endogenous peptide ligands for the receptors to which these compounds bind is a more recent discovery. It is now appreciated that the body 

PEPTIDES, PROTEINS, AND OTHER AMINO ACID DERIVATIVES 

Interferons were originally discovered as proteins that interfered with virus replication. When mice were injected with antibodies to interferons, they became markedly susceptible to virus-mediated disease, including virus-related tumour induction. Interferons can be detected at low levels in most human tissues, but amounts increase upon infection with viruses, bacteria, protozoa, and exposure to certain growth factors. Interferons were initially classified according to the cellular source, but recent nomenclature is based primarily on sequencing data. Thus leukocyte interferon (a mixture of proteins) is now known as interferon alfa, fibroblast interferon as interferon beta, and immune interferon as interferon gamma. 

Enzymes are proteins that act as biological catalysts. They facilitate chemical modification of substrate molecules by virtue of their specific binding properties, which arise from particular combinations of functional groups in the constituent amino acids at the so-called active site. In many cases, an essential cofactor, e.g. NAD+, PLP, or TPP, may also be bound to participate in the transformation. The involvement of enzymes in biochemical reactions has been a major theme throughout this book. The ability of enzymes to carry out quite complex chemical reactions, rapidly, at room temperature, and under essentially neutral conditions is viewed with envy by synthetic chemists, who are making rapid progress in harnessing this ability for their own uses. Several enzymes are currently of importance commercially, or for medical use, and 

Powdered opium, U.S.R, is a light brown, bitter, fine powder, supplied for clinical use in capsule, tablet, or pill form. The average adult dose is 0.06 gram taken orally. This is equivalent to 6 mgm of morphine, the official morphine content of opium being 10% by weight. Opium tincture (Laudanum, deodorized opium tincture), U.S.R, is a hydroalcoholic solution containing 10% of opium (1.0% of morphine). The average adult dose is 0.6 to 1.5 mL (equivalent to 6 to 15 mgm of morphine), taken orally. 

Opium (gum opium) and granulated opium are also official in the U.S.R The dose of either is the same as for the 

OPIUM TINCTURE/PAREGORIC (Opium tincture, deodorized liquid 10 mg anhydrous morphine equivimL, Paregoric liquid 2 mg anhydrous morphine equiviS mL) 

Opium tincture/paregoric is an opioid analgesic that enhances tone in long segments of longitudinal muscle and inhibits propulsive contraction of both circular and longitudinal muscles. Opium tincture is used in acute and nonspecific diarrhea. 

Opioids used for diarrhea include codeine (in doses of 30 mg given three or four times daily) and opium-containing compounds. 

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The second application of the CFTI protocol is the evaluation of the free energy differences between four states of the linear form of the opioid peptide DPDPE in solution. Our primary result is the determination of the free energy differences between the representative stable structures j3c and Pe and the cyclic-like conformer Cyc of linear DPDPE in aqueous solution. These free energy differences, 4.0 kcal/mol between pc and Cyc, and 6.3 kcal/mol between pE and Cyc, reflect the cost of pre-organizing the linear peptide into a conformation conducive for disulfide bond formation. Such a conformational change is a pre-requisite for the chemical reaction of S-S bond formation to proceed. The predicted low population of the cyclic-like structure, which is presumably the biologically active conformer, agrees qualitatively with observed lower potency and different receptor specificity of the linear form relative to the cyclic peptide. 

The principal hormones of the human posterior pituitary include the two nonapeptides, oxytocin [50-56-6] and arginine vasopressin [11000-17-2] (antidiuretic hormone, ADH). Many other hormones, including opioid peptides (see Opioids, endogenous), cholecystokinin [9011-97-6] (CCK) (see Hormones, BRAIN oligopeptides), and gastrointestinal peptides, also have been located in mammalian neurohypophysis (6), but are usually found in much lower concentrations (7). Studies have demonstrated that oxytocin and vasopressin are synthesized in other human organs, both centrally and peripherally, and there is considerable evidence for their role as neurotransmitters (see Neuroregulators) (8). 

Several peptides are related in different ways to these classical opioid peptides. FMREamide (Phe-Met-Arg-Phe-NH2) contains the first four amino acids of enkephalin and is active in various invertebrates (58) FMREamide-related peptides also have been located in the mammalian brain. Although these... 

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. 

At the time of the discovery of Met-enkephalin, its sequence was observed to be identical to that of residues 61—65 contained in the C-fragment of the pituitary hormone p-Hpotropin [12584-99-5] (p-LPH) (see Hormones), first isolated in 1964 (11). In 1976, the isolation of a larger peptide fragment, P-endorphin [60617-12-1] that also displayed opiate-like activity was reported (12). This peptide s 31-amino-acid sequence comprised residues 61—91 of P-LPH. Subsequentiy, another potent opioid peptide, dynorphin [72957-38-17, was isolated from pituitary (13). The first five amino acids (qv) of this 17-amino-acid peptide are identical to the Leu-enkephalin sequence (see Table 1). 

Fig. 2. Schematic drawing of the precursors for opioid peptides. Shaded areas represent the location of sequences of active peptide products which are normally released by trypsin-like enzymes acting on pairs of basic amino acid residues. Precursors are not necessarily drawn to scale.

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... 

The opioid peptides vary in their binding affinities for the multiple opioid receptor types. Leu- and Met-enkephalin have a higher affinity for 5-receptors than for the other opioid receptor types (68), whereas the dynorphin peptides have a higher affinity for K-sites (69). P-Endorphin binds with equal affinity to both p- and 5-receptors, but binds with lower affinity to K-sites (70). The existence of a P-endorphin-selective receptor, the S-receptor, has been postulated whether this site is actually a separate P-endorphin-selective receptor or is a subtype of a classical opioid receptor is a matter of controversy (71,72). The existence of opioid receptor subtypes in general is quite controversial although there is some evidence for subtypes of p- (73), 5-(74), and K-receptors (72,75), confirmation of which may be obtained by future molecular cloning studies. 

B. P. Roques and M. C. FourniH-Zaluski, in R. S. Rapaka and R. L. Hawks, eds.. Opioid Peptides Molecular Pharmacology, Biosynthesis and Analysis, NIDA Research Monograph 70, 1986, p. 128. 

Endogenous opioid peptide released both in the central nervous system and in other apparatuses of the body that have many regulatory functions, including inhibition of pain transmission. 

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