Kappa-opioid receptor activation

Ma GH, Miller R, Kuznestov A et al. Kappa-opioid receptor activates an inwardly rectifying K+ channel by a G protein-linked mechanism coexpression in Xenopus oocytes. Mol Pharmacol 1995 47 1035-1040. 

Rusin, K. I., Giovannucci, D. R., Stuenkel, E. L., and Moises, H. C. (1997). Kappa-opioid receptor activation modulates Ca2+ currents and secretion in isolated neuroendocrine nerve terminals. J. Neurosci. 17, 6565-6574. 

Anzini M, Canullo L, Braile C, et ah Synthesis, biological evaluation, and receptor docking simulations of 2-[(acylamino)ethyl]-1,4-benzodiazepines as kappa-opioid receptor agonists endowed with antinociceptive and antiamnesic activity. J Med Chem 46 3833-3864, 2003... 

The mu, delta and kappa opioid receptors are coupled to G° and G proteins and the inhibitory actions of the opioids occur from the closing of calcium channels (in the case of the K receptor) and the opening of potassium channels (for /i, d and ORL-1). These actions result in either reductions in transmitter release or depression of neuronal excitability depending on the pre- or postsynaptic location of the receptors. Excitatory effects can also occur via indirect mechanisms such as disinhibition, which have been reported in the substantia gelatinosa and the hippocampus. Flere, the activation of opioid receptors on GABA neurons results in removal of GABA-mediated inhibition and so leads to facilitation. 

As Shown in table 2, a comparative dose of 10 n units of PCP-like activity inhibited 3H-PCP binding in rat brain membranes, but did not inhibit binding of 3 H - d i hydromorphi ne, 3H - D - a 1 a2 - D -1 eu5-enkephalin, 3H-ethylketocyclazocine, 3H-diazepam, or -neurotensin. These results indicate that the active material is specific and selective from PCP receptors, as binding to the mu, delta, and kappa opioid receptors was unaffected, as was binding to benzodiazepine and neurotensin receptors. 

Paterlini G, Portoghese P, Ferguson D. Molecular simulation of dynorphin A-(1—10) binding to extracellular loop 2 of the kappa opioid receptor. A model for receptor activation. J Med Chem 1997 40 3254-3262. 

Chu P, Murray S, Lissin D, von Zas-trow M. Delta and kappa opioid receptors are differentially regulated by dyna-min-dependent endocytosis when activated by the same alkaloid agonist. J Biol Chem 1997 272 27124-27130. 

The 1,2-aminoamides are now established as a chemical series with several highly selective kappa opioid receptor agonists. However, the biological activity of 1,2-aminoamides is not restricted to kappa analgesics. Several related structures exhibit biological activity in other systems of importance and interest. In order to appraise the significance of this chemical class and to put the SAR for kappa receptor activity into context, a selection of these compounds is discussed here. This is not a comprehensive literature review but rather a selection of a few compounds to illustrate the broad range of medieinal activity exhibited by these somewhat similar chemical structures. 

In contrast to the analgesic role of leu- and met-enkephalin, an analgesic action of dynorphin A—through its binding to (kappa) opioid receptors—remains controversial. Dynorphin A is also found in the dorsal horn of the spinal cord, where it may play a critical role in the sensitization of nociceptive neurotransmission. Increased levels of dynorphin can be found in the dorsal horn after tissue injury and inflammation. This elevated dynorphin level is proposed to increase pain and induce a state of long-lasting hyperalgesia. The pronociceptive action of dynorphin in the spinal cord appears to be independent of the opioid receptor system but dependent on the activation of the bradykinin receptor. Moreover, dynorphin A can bind and activate the N -methyl-D-aspartate (NMDA) receptor complex, a site of action that is the focus of intense therapeutic development. 

Cosentino M, Marino F, De Ponti F et al (1995) Tonic modulation of neurotransmitter release in the guinea-pig myenteric plexus effect of mu and kappa opioid receptor blockade and of chronic sympathetic denervation. Neurosci Lett 194 185-8 Costa M, Majewski H (1988) Facilitation of noradrenaline release from sympathetic nerves through activation of ACTH receptors, B-adrenoceptors and angiotensin II receptors. Br J Pharmacol 95 993-1001... 

Schlosser B, Kudernatsch MB, Sutor B et al (1995) Delta, mu and kappa opioid receptor agonists inhibit dopamine overflow in rat neostriatal slices. Neurosci Lett 191 126-30 Schwertfeger E, Klein T, Vonend O et al (2004) Neuropeptide Y inhibits acetylcholine release in human heart atrium by activation of Y2-receptors. Naunyn-Schmiedeberg s Arch Pharmacol... 

Ronken E, Mulder AH, Schoffelmeer ANM (1993) Chronic activation of mu and kappa-opioid receptors in cultured catecholaminergic neurons from rat brain causes neuronal supersensitivity without receptor desensitization. J Pharmacol Exp Ther 268 595-9 Schlicker E, Kathmann M (2001) Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci 22 565-572... 

Hampson, R. E., Mu, J., and Deadwyler, S. A. (2000). Cannabinoid and kappa opioid receptors reduce potassium K current via activation of G(s) proteins in cultured hippocampal neurons. 

Agonist occupancy of GPCRs, such as the delta opioid receptor, leads to physiological effects through interactions with heterotrimeric G proteins. Such G proteins consist of a Ga subunit and its Gpy dimeric partner. There are four major families of Ga proteins with different profiles of effector interaction 1) Gas, which activate adenylyl cyclase 2) Gai/o, so-called inhibitory G proteins named for their ability to inhibit adenylyl cyclase, but interact with many effectors 3) Gaq/11, which activate phospholipase C- 3 (PLC- 3) and 4) Gal2/13, which may regulate small GTP-binding proteins. Delta opioid receptors, like mu and kappa opioid receptors, couple to mem-... 

Further studies in mouse vas deferens indicated that DPI-3290 is also active at mu opioid receptors. The intrinsic activity of DPI-3290 at mu opioid receptors was determined in the presence of the highly selective delta opioid receptor antagonist TIPP (H-Tyr-Tic-Phe-Phe-OH) (3 pM) and the selective kappa opioid receptor antagonist nor-BNI (15 nM). Under these conditions, DPI-3290 again caused concentration-dependent inhibition of muscle contraction with a corresponding IC50 value of 6.2 2.0 nM. Although far less potent at kappa opioid receptors in comparison to its intrinsic activity at mu... 

Recently, Sedqi et al. [24] were able to clone a delta opioid receptor complementary DNA by expression of cDNA library from activated thymocytes in Cos 7 cells, whose amino acid sequence was similar to the neural counterpart. Interestingly, they also observed that transcripts for kappa and mu opioid receptors were not detected in thymocytes. Furthermore, Gave-riaux et al. [25] demonstrated transcripts for the delta opioid receptor in T-lymphocyte, B-lymphocyte, and monocyte cell lines, as well as in murine splenocytes. However, they observed that the kappa opioid receptor transcript was only found in B-cell lines. These studies may suggest a selective expression of the delta opioid receptor in specific cells and tissues of the immune system and suggests specialized functions in different anatomical regions. 

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