Morphine coupling

Although this isoquinoline at first bears little structural resemblance to morphine (108), careful rearrangement of the structure (A) shows the narcotic to possess the benzylisoquinoline fragment within its framework. Indeed, research on the biogenesis of morphine has shown that the molecule is formed by oxidative coupling of a phenol closely related to papaverine. 

Figure 11.12 GC analysis of (a) urine sample spiked with opiates 3 p.g/ml) and (b) blank urine sample. Peak identification is as follows 1, dihydrocodeine 2, codeine 3, ethylmor-phine 4, moipliine 5, heroin. Reprinted from Journal of Chromatography, A 771, T. Hyotylainen et al., Determination of morphine and its analogues in urine by on-line coupled reversed-phase liquied cliromatography-gas clrromatography with on-line derivatization, pp. 360-365, copyright 1997, with permission from Elsevier Science.

Similar to endogenous opioids, opiates like morphine and other synthetic opioids activate G-protein-coupled receptors which couple to G-proteins of the Gi/0 family. 

Specific IgE Assay. Two radioimmunoassays are available in France using a quaternary ammonium compoimd coupled to Sepharose [30, 31]. The sensitivity of these tests was equivalent at 88%, the specificity reaches 90%. A morphine-based immunoassay has been proposed in Australia [14]. More recently, Ebo et al. [32] investigated a rocuronium ImmimoCAP and set the sensitivity at 85%, the specificity being absolute, provided an assay-specific decision threshold is applied. An ImmimoCAP (Phadia A) is available. 

Peterson PK, Sharp BM, Gekker G, Jackson B, Balfour HH Jr (1991) Opiates, human peripheral blood mononuclear cells, and HIV. Adv Exp Med Biol 288 171-178 Peterson PK, Gekker G, Schut R, Hu S, Balfour HH Jr, Chao CC (1993) Enhancement of HlV-1 replication by opiates and cocaine the cytokine connection. Adv Exp Med Biol 335 181-188 Peterson PK, Gekker G, Hu S, Sheng WS, Molitor TW, Chao CC (1995) Morphine stimulates phagocytosis of Mycobacterium tuberculosis by human microglial cells involvement of a G protein-coupled opiate receptor. Adv Neuroimmunol 5 299-309 Peterson PK, Molitor TW, Chao CC (1998) The opioid-cytokine connection. J Neuroimmunol 83 63-69... 

There are a number of side-effects of opiates that are due to their actions on opiate receptors outside the central nervous system. Opiates constrict the pupils by acting on the oculomotor nucleus and cause constipation by activating a maintained contraction of the smooth muscle of the gut which reduces motility. This diminished propulsion coupled with opiates reducing secretion in the gut underlie the anti-diarrhoeal effect. Opiates contract sphincters throughout the gastrointestinal tract. Although these effects are predominantly peripheral in origin there are central contributions as well. Morphine can also release histamine from mast cells and this can produce irritation and broncho-spasm in extreme cases. Opiates have minimal cardiovascular effects at therapeutic doses. 

Rectal Administration. The administration of drugs by a solid rectal dosage form (i.e., suppositories) results in a wide variability in the rate and extent of absorption in children [79]. This fact, coupled with the inflexibility of a fixed dose, makes this a route that should not be promoted for pediatric patients. At least one death involving a 7-month-old infant can be directly attributed to the use of solid rectal dosage form of a therapeutic dose of morphine [80]. 

The multiplicity of G proteins coupled to opiate receptors may explain how different opiates can bind to the same receptor yet induce different cellular responses. For example, morphine binds to the cloned rat fi receptor expressed in HEK 293, CHO and COS-7 cells and inhibits cAMP accumulation [80-82]. Morphine can be continuously applied to the cells for up to 16 h, and the potency and magnitude of morphine inhibition of adenylyl cyclase does not diminish [80, 81]. In contrast, the opiate sufentanil can bind to the same cloned fi receptor in HEK 293 cells to inhibit cAMP accumulation. However, sufentanil s actions rapidly desensitize [83]. Since both compounds bind to the same receptor, and the fi receptor is the only receptor these drugs can interact with in these cells, the ability of these two full agonists to differentially regulate the fi receptor must be due to their abilities to affect separate adaptive processes in these cells. 

The ability of morphine to desensitize other neurotransmitter receptors coupled to K+ channels may cause long-term consequences in the activity of neurons. The uncoupling of K+ channel from non-opioid receptors that normally tonically inhibit cell firing could result in an increase in the basal firing of the cells. Changes in the set point of neuronal firing could influence gene expression in the cells and alter the molecular properties of the neurons. 

While chronic morphine treatment uncouples the // receptor from K+ channels, it did not affect the coupling of ft receptors to adenylyl cyclase. Pretreatment of the cloned ft receptor expressed in HEK 293, AtT-20, CHO and COS cells with morphine or DAMGO for up to 16h did not alter the subsequent ability of fi agonists to inhibit cAMP accumulation [25, 65, 80-82]. These findings suggest that morphine treatment induces a selective desensitization of the coupling of the fi receptor to K+ channels. 

The maintenance of fi receptor/adenylyl cyclase coupling indicates that chronic morphine treatment does not downregulate the fi receptor to the extent of abolishing function. This has been confirmed by immunohistochemical studies which have shown that morphine treatment does not internalize or downregulate the cloned fi receptor [80, 89]. 

If ft receptors couple to K+ channels and adenylyl cyclase via different G proteins, it is possible that chronic morphine treatment uncouples the receptor from those G proteins linked to the K+ channel and not those coupling fi receptors to adenylyl cyclase. Such a hypothesis would require that G proteins couple to different intracellular domains of the fi receptor so that interaction of G proteins with some domains could be blocked by post-translational events, such as phosphorylation, whereas binding of G proteins to other fi receptor domains would not be affected. 

Buprenorphine does not cause dependence in humans [96]. Unbke morphine, buprenorphine desensitizes the /< receptor coupling to adenylyl cyclase [80]. The desensitization occurs in the absence of any receptor internalization or downregu-lation [80]. The desensitization of the /x receptor may be the underlying basis for why buprenorphine does not cause a heightened adenylyl cyclase activity in // receptor-responsive cells. Buprenorphine s unique cellular regulation of the // receptor may explain its ability to be a non-addictive analgesic as well as its usefulness in treating opiate dependence. 

Per-O-acylated glycosyl iodides are stable at room temperature and can be purified on a silica gel column and stored at 0 °C. Stachulski and coworkers [202] synthesized methyl 2,3,4-tri-O-pivaloyl-glucopyranuroate iodide, which is a stable solid at 20 °C and can be stored for months at room temperature or for more than a year at 0 °C. The X-ray crystal structure of this compound, the first one of this class, shows a typical chair structure. Importantly, such a disarmed and stable iodide can be coupled with primary and secondary steroidal alcohols using I2 as a promoter, as demonstrated by the synthesis of morphine-6-glucuronide, an analgesic [202], The glycosyl donor ability... 

Phenolic oxidative coupling the biosynthesis of tubocurarine and morphine... 

In Box 9.4, we saw that tetrahydroisoquinoline alkaloids with appropriate phenol substituents could be involved in radical coupling processes. The complex alkaloids tubocurarine and morphine are derived in nature from simpler tetrahydroisoquinoline alkaloids. 

Ga-GDP has no affinity for the effector protein and reassociates with the p and Y subunits (A). G-proteins can undergo lateral diffusion in the membrane they are not assigned to individual receptor proteins. However, a relation exists between receptor types and G-protein types (B). Furthermore, the a-subunits of individual G-proteins are distinct in terms of their affinity for different effector proteins, as well as the kind of influence exerted on the effector protein. G -GTP of the Gs-protein stimulates adenylate cyclase, whereas G -GTP of the Gr protein is inhibitory. The G-protein-coupled receptor family includes muscarinic cholinoceptors, adrenoceptors for norepinephrine and epinephrine, receptors for dopamine, histamine, serotonin, glutamate, GABA, morphine, prostaglandins, leukotrienes, and many other mediators and hormones. 

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. 

C. The purpose of this question is to clarify the cellular mechanism of analgesia produced by morphine. First, morphine blocks the transmission of nociceptive impulses. In that case, the relevant question is how nociceptive impulses are transmitted via the release of pronociceptive neurotransmitters. The question then is to determine which intracellular process favors a block of release of neurotransmitters. The correct answer is C because calcium is required for neurotransmitter release. Blocking potassium efflux and increasing calcium channel phosphorylation produce functional depolarization and neurotransmitter release. Opioids are coupled to Gj (inhibitory proteins) that decrease cAMP. 

There are various opioid receptors the three major classes of opioid receptors are mu (p), delta (5) and kappa (k) receptors. The p, receptor is the principal pain-modulating site in the CNS, mediating the action of morphine. There is considerable interest in the K receptor, which mediates a sedating analgesia with decreased addiction liability and respiratory depression and which allows for some structural flexibility. Unfortunately, the K receptor seems to be coupled to the sigma (a) receptor, which is implicated in psychotomimetic and dysphoric side effects. 

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