Kappa receptors activation

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. 

Kappa receptor activation does not appear to be responsible for dependence, euphoria, or effects on smooth muscle. Increases in cerebral blood flow and (possibly) increased intracranial pressure result from the respiratory depressant actions of opioid analgesics. The latter effects are due to increased arterial PrOj, which results from mu receptor inhibition of the medullary respiratory center. However, the activation of kappa receptors contributes to analgesia at the spinal level and is probably responsible for sedative actions of the opioids. The answer is (D). Codeine and possibly nalbuphine could decrease gastrointestinal peristalsis but not without marked side effects (and a prescription). Dextromethorphan is a cough suppressant. The other two drugs listed are opioids with antidiarrheal actions. Diphenoxylate is not available over-the-counter since it is a constituent of a proprietary combination that includes atropine sulfate (Lomotil). Loperamide is available over-the-counter. The answer is (D). 

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. 

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. 

Srivastava S, Toraldo G, Weitzmann MN, Cenci S, Ross FP, Pacifici R (2001) Estrogen decreases osteoclast formation by down-regulating receptor activator of NF-kappa B ligand (RANKL)-induced JNK activation. J Biol Chem 276 8836-8840... 

Palmqvist P, Persson E, Conaway HH, Lerner UH (2002) IL-6, leukemia inhibitory factor, and oncostatin M stimulate bone resorption and regulate the expression of receptor activator of NF-kappa B ligand, osteoprotegerin, and receptor activator of NF-kappa B in mouse calvariae. J Immunol 169 3353-3362... 

Sawynok J. (1995). Pharmacological rationale for the clinical use of caffeine. Drugs. 49(1) 37-50. Sawynok J. (1998). Adenosine receptor activation and nociception. Eur J Pharmacol. 347(1) 1-11. Schlaepfer TE, Strain EC, Greenberg BD, Preston KL, Lancaster E, Bigelow GE, Barta PE, Pearlson GD. (1998). Site of opioid action in the human brain mu and kappa agonists subjective and cerebral blood flow effects. Am J Psychiatry. 155(4) 470-73. 

Both U-62066 (spiradoline) (10) and PD 117302 (12) are racemic mixtures of two enantiomers. The kappa opioid activity has been shown to reside in the (—) enantiomer, and in the case of U62066 the (-h) enantiomer is a weak mu receptor agonist [49, 50]. (See above for discussion on absolute stereochemistry.)... 

Mu and kappa receptor agonists have been shown to affect central dopaminergic activity in rodents in vivo and in vitro [78, 79]. This has been investigated with RP 60180 (51), which decreases dopamine (DA) utilization in rat prefrontal cortex and in the striatum (by 30—35 % and 10 % respectively at 1-2.5 mg/kg s.c.) whereas the mu agonist morphine causes a significant increase (90-150% and 30 40% respectively at 5 mg/kg), an effect which is abolished by RP 60180 (1 2.5 mg/kg) [80]. 

In the above discussion on the mu/kappa receptor selectivity of the U-50488 (5) series, the steric properties of the tertiary amine and the distance between the amide and the aromatic ring were cited as important factors. This has been exploited by the Upjohn company to give the arylformamide-dimethyl-amine derivative (52) which is an analgesic in the mouse tail flick test (ED50 = 0.2 mg/kg s.c.) and causes mu-opioid like side-effects such as Straub tail, arched back and increased locomotor activity [81]. These behavioural effects and the association constant for the morphine receptor of compound... 

Activation of kappa receptors also produces analgesia, but it simultaneously induces nausea and dysphoria. Kappa receptors are located mainly on pain neurons located in the spinal cord and, to a lesser extent in the brain. They bind to an endogenously occurring ligand called dynorphin. 

Buprenorphine is derived from thebaine. It is a partial mu agonist with kappa antagonist activity. Buprenorphine has 25 to 50 times the potency of morphine. It is used to produce a longer-lasting analgesia than morphine. Effects of buprenorphine last longer because it is released more slowly from mu receptors than morphine. It is available as an injectable for intramuscular (IM) or intravenous administration in a 1-ml solution containing 0.3 mg buprenorphine (as buprenorphine HC1) for the relief of moderate to severe pain. It is also available to treat opioid dependence in the formulation of a tablet,51 alone or in combination with naloxone, in 2- or 8-mg... 

Table 8.1 shows a selective timeline of the evaluation, abuse, and regulation of butorphanol, an opioid with mixed activity at mu and kappa receptors. The most salient aspects of the drug s recent history can be summed up in terms of two questions ... 

Kim G. M., Xu J., Xu J. M., Song S. K., Yan P., Ku G., Xu X. M., and Hsu C. Y. (2001). Tumor necrosis factor receptor deletion reduces nuclear factor-kappa B activation, cellular inhibitor of apoptosis protein 2 expression, and functional recovery after traumatic spinal cord injury. J. Neurosci. 21 6617-6625. 

A new addition to this category is buprenorphine (Buprenex). This drug partially activates mu receptors but is an antagonist at kappa receptors. Because of these selective effects, buprenorphine has been advocated not only as an analgesic, but also as a treatment for opioid dependence and withdrawal.26 84 The use of this drug in treating opioid addiction is discussed in more detail later in this chapter. 

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. 

All opioids produce their effect by activating one or more of the three types of receptors. Thus analgesia involves the activation of the mu receptors that are located mainly at supraspinal sites and kappa receptors in the spinal cord delta receptors may also be involved but their relative contribution is unclear. Nevertheless, the actions of the opioids on these receptors is complex, as there is evidence that the same substance may act as a full agonist, or as an antagonist at different sites within the brain. 

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. 

LPL M-CSFR MHC MHC-II MMCP MMP NG2 PDGF PPAR RANK Sca-1 SM22 L lipoprotein monocyte - colony stimulation factor receptor myosin heavy chain MHC class II mouse mast cell protease metalloproteinase proteoglycan heparan-sulfate related to pericytes activity platelet-derived growth factor peroxisome proliferator-activated receptor gamma receptor activator of NF-kappa 3 stem cell antigen 1 smooth cell protein structurally related to calponin, both actin and tropomyosin ligands... 

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