Kappa receptors opioids

Tu B, Timofeeva O, Jiao Y et al (2005) Spontaneous release of neuropeptide Y tonically inhibits recurrent mossy fiber synaptic transmission in epileptic brain. J Neurosci 25 1718-29 Ueda H, Fukushima N, Ge M et al (1987) Presynaptic opioid kappa-receptor and regulation of the release of Met-enkephalin in the rat brainstem. Neurosci Lett 81 309-13 van den Pol AN, Gao XB, Obrietan K et al (1998) Presynaptic and postsynaptic actions and modulation of neuroendocrine neurons by a new hypothalamic peptide, hypocretin/orexin. J Neurosci 18 7962-71... 

Freye E, Boeck G, Schaal M, Ciaramelli F (1986) The benzodiazepine (-l-)-tifluadom (KC-6128), but not its optical isomer (KC-5911) induces opioid kappa receptor-related EEG power spectra and evoked potential changes. Pharmacology 33 241-248... 

OTHER REVIEWS OF THE OPIOID LITERATURE INTRODUCTION SELECTIVE KAPPA OPIOID LIGANDS KAPPA RECEPTOR SUBTYPES... 

A comprehensive review of receptor selective opioid peptide analogues by Schiller [7] appeared in the previous volume of this Series and for this reason the present chapter describes only non-peptide structures. A leading review which introduces kappa opioid analgesics was written by Horwell in 1988 [8] and a subsequent article focusing on kappa receptors and analgesia by Millan appeared in 1990 [9]. 

The biochemical and pharmacological properties of the kappa receptor and the differences between the kappa, mu and delta receptors have been reviewed elsewhere. The reader is directed to the opioid review articles by Rees and Hunter (1990) [4], Casy (1989) [3] and Leslie (1987) [10] and also to two shorter reviews which deal specifically with kappa agonists the review by Horwell published in 1988 entitled Kappa Opioid Analgesics [8] and the review by Millan in 1990 on kappa opioid receptors and analgesia [9]. An account of the medicinal chemistry of selective opioid agonists and antagonists was published in 1990 by Zimmerman and Leander [5]. 

As discussed above, the discovery by the Upjohn Company in 1982 of U-50488 (5) was a milestone achievement in opioid research. This compound has significantly greater selectivity for the kappa opioid receptor than the previously used ketazocine (2) or EKC (3) and its widespread use in opioid research to study the properties of the kappa receptor has led to its being generally regarded as the prototype non-peptide kappa selective agonist. 

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 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... 

The majority of studies aimed at preparing kappa-selective opioids have used U-50488 (5) as the chemical lead and, as the above discussion shows, this has proved to be a highly productive approach. However, as was pointed out above, there are other structures [EKC (3), tifluadom (6) and the peptide dynorphin (7)] which have been reported to bind to the kappa receptor, albeit with poor opioid receptor subtype selectivity. Some attempts have been made to develop kappa-selective ligands from these structures and they are summarized here. 

Opioid receptors are found in the dorsal horn as well as in other areas throughout the spinal cord and brain. Three major classes of opioid receptors exist mu receptors (/r), kappa receptors (k) and delta... 

Dooley, C. and Houghten, R. (Torrey Pines Institute for Molecular Studies) Novel kappa receptor selective opioid peptides, W09640206 (1996), US5610271 (1997). 

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 ... 

The existence of several classes of opioid receptors has therefore lead to the development of drugs that are somewhat more selective in the receptor class or subclass that they stimulate. In particular, drugs that selectively stimulate kappa or delta receptors may still provide sufficient analgesia, but will be less likely to provoke problems like respiratory depression and opioid abuse if they avoid or even block (antagonize) the mu receptors. Certain opioid drugs, for example, stimulate kappa receptors while avoiding or blocking... 

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. 

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. 

Today, we know that there are three types of opioid receptors—mu, delta, and kappa receptors [see review 3]. Proenkephalin contains six copies of Met-enkephalins and one copy of Leu-enkephalin. Enkephalins, especially Leu-enkephalin, are believed to be selective to delta receptors. Opiomelano-cortin contains (3-endorphin that has the Met-enkephalin at its amino terminus. (3-Endorphin is a nonselective ligand for mu and delta receptors. 

Prodynorphin contains three copies of Leu-enkephalin with carboxy-termi-nus extended polypeptides of various lengths known as dynorphin A (or dynorphin 1-17), dynorphin B (dynorphin 1-13), or a- and 3-neoendorphin. These peptides derived from prodynorphin are selective to kappa receptors and can also be further broken down to Leu-enkephalin. The identification of the delta receptor (or the enkephalin receptor) was a direct consequence of the discovery of enkephalins. This chapter will review the major events that are important for the identification of delta receptors and the subsequent cloning of delta receptor genes, and eventually all other opioid receptor genes. 

The cloning of the delta receptor set in motion a competitive race to identify other members of the opioid receptor family. Homologous orphan clones were quickly assessed for opioid receptor binding properties, which resulted in the identification of the kappa receptor and reassignment of an orphan clone as the delta opioid receptor [31]. PCR, genomic, and cDNA screens revealed the mu opioid receptor and an extremely abundant orphan member, named opioid receptor-like (ORL-1) receptor (reviewed by Massotte and Kieffer [30]). 

The binding site crevice was probed by cysteine accessibility mapping, where each amino acid from TM6 was replaced by a Cys residue and tested for reactivity to methanethiosulfonate ethylammonium [38]. The comparative study accross mu, delta, and kappa receptors showed a water-accessible surface on the extracellular face of the helix for all opioid receptors and located above the Pro kink (Ile277 and Phe280 to Leu286 in the delta receptor). The data were consistent with the notion of an opioid binding pocket penetrating the upper half of the helical bundle (see Fig. 1A). 

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