Opiates receptors

Diphenoxylate Hydrochloride. l-(3-Cyano-3,3-diphenylpropyl)-4-phenyl-4-piperidinecarboxyhc acidmonohydrochlorhydrate [3810-80-8] (Lomotil) (13) is a white, odorless, crystalline powder that melts at 220—226°C. It is soluble ia methanol, spariagly soluble ia ethanol and acetone, slightly soluble ia water and isopropyl alcohol, freely soluble ia chloroform, and practically iasoluble ia ether and hexane. The method of preparation for diphenoxylate hydrochloride is available (11). Diphenoxylate hydrochloride [3810-80-8] (13) is an antidiarrheal that acts through an opiate receptor. It has effects both on propulsive motility and intestinal secretion. Commercial forms are mixed with atropiae to discourage abuse. 

The BZ stmcture also has provided a molecular scaffold for a number of peptide receptor ligands (26). Antagonists for the cholecystokinin (CCK-A) receptor, eg, devazepide (65), the thyrotropin-releasing hormone (TRH) receptor, eg, midazolam (66), and the /i -opiate receptor, eg, tifluadom (67), as well as a series of ras famyl transferase inhibitors, eg, BZA-2B (68) (30) have been identified (Table 4). 

Opiates iateract with three principal classes of opioid GPCRs )J.-selective for the endorphiQS,5-selective for enkephalins, and K-selective for dynorphias (51). AU. three receptors have been cloned. Each inhibits adenylate cyclase, can activate potassium channels, and inhibit A/-type calcium channels. The classical opiates, morphine and its antagonists naloxone (144) and naltrexone (145), have moderate selectivity for the. -receptor. Pharmacological evidence suggests that there are two subtypes of the. -receptor and three subtypes each of the 5- and K-receptor. An s-opiate receptor may also exist. 

SKIP produces its effects through two classes of GPCR, SRIF-1 and SRIF-2 that are structurally related to cloned opiate receptors. The agonists,... 

Administration of naloxone prevents or reverses the effects of the opiates. The exact mechanism of action is not fully understood, but it is believed that naloxone reverses opioid effects by competing for opiate receptor sites (see Chap. 19). If the individual has taken or received an opiate, the effects of the opiate are reversed. 

Zadina JE, Martiri Schild S, Gerall AA, et al Endomorphins novel endogenous mu-opiate receptor agonists in regions of high mu-opiate receptor density. Ann N Y... 

Giimm MC, Ben-Baruch A, Taub DD, Howard OM, Resau JH, Wang JM (1998) Opiates transde-activate chemokine receptors delta and mu opiate receptor-mediated heterologous desensitization. J Exp Med 188(2) 317-325... 

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... 

Uhl, GR, Childers, S and Pasternak, G (1994) An opiate receptor gene family reunion. Trends Neurosci. 17 89-93. 

The actions of all clinically used opiates can now be explained in terms of their acting as agonists at one of the four opiate receptors found in the brain, spinal cord and peripheral nervous system. All four receptors are inhibitory (Table 21.2). 

The opiate receptors in the spinal cord are predominantly of the mu and delta type and are found in the C-fibre terminal zone (the substantia gelatinosa) in the superficial dorsal horn. Considerable numbers of ORL-1 receptors are also found in this area. Up to 75% of the opiate receptors are found presynaptically on the C-fibre terminals and when activated inhibit neurotransmitter release. The opening of potassium channels will reduce calcium flux in the terminal and so there will be a resultant decrease in... 

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. 

Heroin (diacetylmorphine) a highly lipophilic drug but has very weak or no affinity for opiate receptors. It penetrates the brain rapidly whereupon it is metabolised to morphine which then binds to the mu receptor. 

There are now selective antagonists for all three opiate receptors (see Table 21.2) but with the exception of naloxone they are experimental tools for probing the functional roles of the opiate receptors. Naloxone is a potent competitive antagonist at all three receptors with highest affinity for the mu receptor. It will rapidly reverse all opiate... 

Opiates produce more discreet inhibitory effects since they bind to and activate inhibitory opioid receptors which, due to their restricted distribution, cause less widespread effects than those of the barbiturates and alcohol. Activation of the opioid receptors leads to a decrease in release of other neurotransmitters (glutamate, NA, DA, 5-HT, ACh, many peptides, etc.) and direct hyperpolarisation of cells by opening of K+ channels and decreasing Ca + channel activity via predominant actions on the mu opiate receptor (see Chapter 12). 

P.L. Wood, S.E. Charleson, D. Lane and R.L. Hudgin, Multiple opiate receptors differential binding of mu, kappa and delta agonists. Neuropharmacology, 20 (1981) 1215-1220. 

Vaccarino, F.J. Bloom, F.E. and Koob, G.F. Blockade of nucleus accumbens opiate receptors attenuates intravenous heroin reward in the rat. Psychopharmacology 86 37-42, 1985. 

O DONAHUE has isolated a naturally occurring peptide from brain that can produce responses similar to PCP when administered to animals. The results are reminiscent of the early studies of the opiopeptides that interact with opiate receptors and produce effects like narcotic drugs when administered to animals. 

Cowan, A. Simple in vivo tests that differentiate prototype agonists at opiate receptors. Iife Sci 28 1559-1570, 1981. 

Largent, B.L. Gundlach, A.L. and Snyder, S.H. Psychotomimetic opiate receptors labeled and visualized with (+)-3H-3-(3-hydroxyphenyl)-N-(l-propyl Ipiperidine. Proc Natl Acad Sci USA 81 4983-4987, 1984. 

Phencyclidine (angel dust) sigma "opiate" receptor Visualization by tritiurn-sensitive film. Proc Natl Acad Sci USA 78 5881-5885, 1981. 

Herkenham, M., and Pert, C.B. In vitro autoradiography of opiate receptors in rat brain suggests loci of "opiatergic" pathways. Proc Natl Acad Sci USA 77 5532-5536, 1980. 

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