Kappa-selective opioid receptor

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. 

Three endogenous opioids have been identified enkephalins, dynorphins and beta-endorphins. These opioid peptides selectively bind to the seven transmembrane GPCRs delta (8), kappa (k), and mu (p). Although dynorphin binds predominately to the k receptor, P-endorphines and enkephalins bind to p and 8 opioid receptors. It is important to note that the analgesia induced by opioids is mediated predominately throngh the p opioid receptor. In vitro studies have shown a decrease in the immnne function and proliferation following p-endorphin administration in rodents (Ray and Cohn 1999) and that the immunosuppressive effects by P-endorphins are steroid-independent (Berkenbosch et al. 1984 Nelson et al. 2000). 

Zheng H, Chu J, Qiu Y, Loh HH, Law PY (2008) Agonist-selective signaling is determined by the receptor location within the membrane domains. Proc Natl Acad Sci USA 105 9421-9426 Zhu Y, Hsu MS, Pintar JE (1998) Developmental expression of the mu, kappa, and delta opioid receptor mRNAs in mouse. J Neurosci 18 2538-2549... 

The relative extent of the unwanted effects caused by selective agonists at the different opioid receptors is of great importance in determining if non-mu opioids will have better spectra of actions as compared to morphine. However, there are good indications that the kappa and delta receptor agonists cause less respiratory depression than mu... 

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. 

Nishi M., Takeshima H., Fukada K., Kato S., Mori K. cDNA cloning and pharmacological characterization of an opioid receptor with high affinities for kappa-subtype selective ligands. FEBS Lett. 330 77, 1993. 

Collins S.L., Kunko P.M., Ladenheim B., Cadet J.L., Carroll F.I., Izenwasser S. Chronic cocaine increases kappa-opioid receptor density lack of effect by selective dopamine uptake inhibitors. Synapse. 45 153, 2002. 

L. (1996) Synthesis, biological evaluation, and quantitative receptor docking simulations of 2-[(acylamino) ethyl]-l,4-benzodiazepines as novel tifluadom-like ligands with high affinity and selectivity for kappa-opioid receptors. Journal of Medicinal Chemistry, 39, 860-872. 

Negus SS, Henriksen SJ, Mattox A, Pasternak GW, Portoghese PS, Takemori AE, Weinger MB, Koob GF. (1993). Effect of antagonists selective for mu, delta, and kappa opioid receptors on the reinforcing effects of heroin in rats. J Pharmacol Exp Ther. 265(3) 1245-52. 

It is now widely accepted that there are at least three opioid receptor sub-types, mu kappa and delta. During the last decade increasing evidence has accumulated to support the hypothesis that a selective kappa opioid agonist will be a powerful analgesic without the clinically limiting side-effects that characterise morphine (e.g., respiratory depression, constipation, addiction)... 

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. 

Table 3.4. OPIOID RECEPTOR BINDING SELECTIVITY OF ZT-52656A (42) COMPARED WITH OTHER KAPPA-SELECTIVE AGONISTS [63]...

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. 

Barber, A.,Gottschlich, R. Novel developments with selective, non-peptidic kappa-opioid receptor agonists, Exp. Opin. Invest. Drugs 1997, 6, 1354-1368. 

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

---