Opiate activity

Opiates activate the chemoreceptor trigger zone in the medulla (by disinhibition) to cause nausea and vomiting, and cough suppression also occurs because of the inhibitory effects of opiates on the brainstem nuclei in the cough reflex pathway. Dextromethorphan is the non-opiate isomer of the opiate levorphanol and is an effective cough suppressant. 

Li, C.H., and Chung, D. Isolation and structure of an untria-kontapeptide with opiate activity from camel pituitary glands. Proc Natl Acad Sci USA 73 1145-1148, 1976. 

DiMaio J, Schiller PW. A cyclic enkephalin analog with high in vitro opiate activity. Proc Natl Acad Sci USA 1980 77 7162-7166. 

Another important but infrequent modification of peptides is a-N-acetylation (Figs 18-5,18-7). During POMC processing, a-N-acetylation greatly increases the skin-darkening potency of ACTH(1-13)NH2 while abolishing both the adrenal steroidogenic potency of ACTH and the opiate activity of (3-endorphin [2]. The enzyme(s) responsible for this modification has not yet been purified or cloned. 

Structures of Peptoids with a,-Adrenergic and p-Opiate Activity (as Reported in ref. 36)... 

Rigid Geometry Studies of Enkephalin The enkephalins are linear pentapeptides, H-Tyr-Gly-Gly-Phe-Met-NH2 (see Figure 2a.) and H-Tyr-Gly-Gly-Phe-Leu-NH2, which bind to several classes of opiate receptors in the mammalian brain including the same receptor as morphine(26,27). Enkephalins have drawn the interest of theoretical biophysicists for two reasons. First, because of their natural opiate activity, it is hoped that improved analgesics can be developed. Second, as pentapeptides, enkephalins are small enough that the molecule can be examined theoretically without excessive expense of computer time. 

Meperidine (Schedule II) is a synthetic analgesic with opiate activity. It has 10-20% of the potency of morphine with all of the addictive side effects. It has a rapid onset of action and duration which makes its useful for relieving the pain associated with labor or as a preanesthetic before surgery. Its biotransformation produces normeperidine which has been associated with seizures. It was a botched clandestine attempt to synthesize a meperidine modification which produced the toxic drug that induced parkinson-type destruction of DA neurons in its users. 

Scientific research has shown that methadone and other opiates have specific areas, or sites, that they attach to in order to exert their influence on the brain and body. These sites, called receptors, are classified as mu, delta, and kappa, depending on what body functions they influence. Opiate activation of mu and delta receptors seems to influence mood, respiration, pain, blood pressure, and gastrointestinal functions. Kappa receptors appear to be more involved in the perception and aversion to pain. The degree of methadone s effect on these receptors can vary widely between individuals, however, there are certain effects that are almost universal. 

Tome, D., Dumontier, A.M., Hautefeuille, M., and Desjeux, J.F. 1987. Opiate activity and transe-pithelial passage of intact beta-casomorphins in rabbit ileum. Am. J. Physiol. 253, G737-G744. 

Like morphine, most analgesically active morphinans bear an oxygen function, usually as hydroxyl, in position C-3. The presence of 3-OH or 3-OAc invariably leads to a significant enhancement of opiate activity in these series, whereas 3-OMe affords, at best, a modest activity increase/81 Other 3-position substituents significantly reduce or abolish activity. 

Figure 5.22 Virtual library of 15,625 tripeptoids with potential p-opiate activity containing the active lead compound 5.3.

Leumorphin is a 29-amino-acid peptide first predicted by Yamamoto et al. (139, 140) when sequencing the cloned DNA complementary to porcine hypothalamic mRNA. They synthesized this peptide and found that it has potent opiate activity as predicted (140), and they also proved the existence of this peptide in humans (141). 

Ling N. Solid-phase synthesis of porcine a-endorphin and y-endorphin, two hypothalamic-pituitary peptides with opiate activity. Biochem. Biophys. Res. Commun. 1977 74 248-255. 

Other possible opiate activation sites could involve certain ATPases associated with calmodulin. A growing literature suggests that such Ca2+-dependent regulator proteins (calcium dependent regulator) regulate the activity of a number of enzymes such as phosphodiesterase (93) and adenylate cyclase (94) via the formation of Ca +-CDR -enzyme complexes in response to Ca + fluxes. Thus, they appear to represent a link between different types of cell messenger, namely Ca + and cAMP. It has further been postulated that calmodulin, a CDR protein, is a likely Ca + receptor site (95). These proteins may thus represent an important site for Ca +-opiate interactions, with consequent alteration of enzyme activity. 

Walker, J.M., Bowen, W.D., Patrick, S.L., Williams, W.E., Mascarella, S.W., Bai, X., Carroll, F.I., 1993. A comparison of (-)-de-oxybenzomorphans devoid of opiate activity with their dextrorotatory phenolic counterparts suggests role of sigma-2 receptors in motor function. Eur. J. Pharmacol. 231, 61-68. 

Figure 5-15. Correlation of receptor binding and opiate activity (Creese and Snyder, 1975).

Caseinomorphins. Several peptides with opioid activity have been isolated from enzymatic digests of milk proteins (see Fox and Flynn, 1992). Such peptides were first isolated from enzymatic digests of casein and characterized as a family of peptides containing 4-7 amino acids with a common N-terminal sequence, H.Tyr.Pro.Phe.Pro-, and 0-3 additional residues (Gly, Pro, He), i.e. residues 60-63/6 of -casein, and hence were called caseinomorphins (P-CM) 4 to 7, respectively. P-CM-5 is the most effective of these peptides, which are 300-4000 times less effective than morphine. P-CMs are very resistant to enzymes of the gastrointestinal tract (GIT) and appear in the contents of the small intestine following ingestion of milk. -CN f60-70 also has weak opiate activity but may be hydrolysed to smaller, more active P-CMs by peptidases in the brush border of the GIT. 

Li CH, Lemaire S, Yamashiro D, et al. The synthesis and opiate activity of p-endorphin. Biochem Biophys Res Commun 1976 71 19-25. 

Valorphin, H-Val-Val-Tyr-Pro-Trp-Thr-Gln-OH, a 6-peptide isolated from bovine hypothalamus tissue possessing opiate activity. Valorphin corresponds to the partial sequence 32-38 of the bovine hemoglobin /3-chain, and may belong to the hemor-phins exorphins) [V. Brand et al., Eur. J. Pharmacol. 1986, 125, 309 J. Erch-egyi et al., J. Pept. Protein Res. 1992, 39, 477]. 

Nissan, H.P., J. Lu, N.L. Booth, et al. 2007. A red clover (Trifolium pratense) phase II clinical extract possesses opiate activity. /. Ethnopharmacol. 112(1) 207-210. 

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. 

Although electrical shock has been used widely as a nociceptive stimulus for evaluating opiate activity, problems do arise in controlling the intensity of stimulus thus, electrode currents and vdtages may be readily maintained where as the impedance of the biological tissues can be extremely variable, thereby producing data of poor reproducibility [29 2]. The variability of data can be reduced when the animals can act as their own controls and also by chronically implanting electrodes subcutaneously sometime before the experiment so that impedance is minimised [SI]. 

Perhaps the most striking example of this upsurge of interest has been in the area of pain research—in its genesis, expression, and, of greatest importance, its intrinsic and extrinsic control. These studies were placed on a molecular footing by the isolation and structure determination of the enkephalins (Hughes et al., 1975b)—two related peptides found in the brain with potent opiate activity—and the concomitant observation that the amino acid sequence of one of these species (met-enkephalin) was present in the protein 3-lipotropin. This led to the discovery of other... 

Fig. 5. Reverse-phase HPLC profile of human CSF following electrical stimulation (juiBondapak Ci8,300 X 4 mm). Opiate activity corresponds to met- and leu-enkephalin together with a third as yet uncharacterized peptide.

---