Opioid agonists kappa-receptor selective

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... 

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. 

Stewart DJ, Fahmy H, Roth BL et al (2006) Bioisosteric modification of salvinorin A, a potent and selective kappa-opioid receptor agonist. Arzneim Forsch 56 269-275... 

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... 

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)... 

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]...

When the efficacy of biphalin-stimulated G protein activation was examined (Table 3) in delta opioid receptor-transfected CHO cells, an efficacy ratio of 0.42 was determined as compared with deltorphin-II and DPDPE, the latter a reference delta-selective agonist. Such low efficacy values suggest that biphalin does not efficiently stimulate the G protein through the delta receptor [9]. Relative affinities of biphalin and morphine for mu, delta, and kappa binding sites in guinea pig brain membranes are shown in Table 4. 

Several nonpeptidic 6-opioid agonists have been synthesized, although none are currently available clinically. These include BW373U86 which is —10 and 20 times more selective for 6-opioid receptor over the p and kappa opioid receptor, respectively, in receptor-binding assays [18]. BW 373U86 also demonstrated high potency (ED50 of 0.2 0.06 nM) in the MVD assay, and its... 

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