Kappa receptor agonists

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]. 

It is a strong kappa receptor agonist and mu receptor antagonist. Its agonistic property is approximately three to four times more than pentazocine and its antagonistic property is approximately 10 times more than pentazocine. It has less abuse liability in comparison to pentazocine. It is useful in postoperative pain, myocardial infarction and labour. 

Scopes, D.I. Recent developments in non-peptide kappa receptor agonists, Drug Fut. 1993, 18, 933-947. 

Mu receptors are almost always located proximally, on the presynaptic side of the synapse. The periaqueductal gray is the region containing the most mu receptors, but they are also found in the superficial dorsal hom of the spinal cord, the external plexiform layer of the olfactory bulb, the nucleus accumbens (an area deeply implicated in the process of addiction), in some parts of the cerebral cortex, and in some of the nuclei of the amygdala. Mu receptors avidly bind enkephalins and beta-endorphin, but they have a low affinity for dynorphins (primarily a kappa receptor agonist).6... 

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 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... 

Iwamoto, E.T. Locomotor activity and antinociception after putative mu, kappa and sigma opioid receptor agonists in the rat Influence of dopaminergic agonists and antagonists. J Pharmacol Exp Ther 217 451-460, 1981. 

Shippenberg T., Heidbreder C. Kappa opioid receptor agonists prevent sensitization to the rewarding effects of cocaine. NIDA Res. Monogr. 153 456, 1994. 

Heidbreder C., Goldberg S., Shippenberg T. The kappa-opioid receptor agonist U-69,593 attenuates cocaine-induced behavioral sensitization in the rat. Brain Res. 616 335, 1993. 

Cao YJ, Bhargava HN. (1997). Effects of ibogaine on the development of tolerance to antinociceptive action of mu-, delta-, and kappa-opioid receptor agonists in mice. Brain Res. 752(1-2) 250-4. Cappendijk SL, Dzoijic MR. (1993). Inhibitory effects of ibogaine on cocaine self-administration in rats. EurJ Pharmacol. 241(2-3) 261-65. 

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]. 

It has been proposed, on the basis of observations made using the benzo-morphan derivative (MR 2034) (8), that all kappa agonists may cause undesired dysophoria and even psychotomimesis in man [27]. Benzomorphans such as MR 2034 with affinity for sigma receptors are well-known to be associated with dysphoria. To date, there has been no report of a dose-ranging clinical study with a truly kappa selective agonist which describes the analgesic effects and the onset of dysphoric symptoms. 

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. 

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.)... 

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. 

Mucha RF, Herz A Motivational properties of kappa and mu opioid receptor agonists studied with place and taste preference conditioning. Psychopharmacology 86 274-280, 1995... 

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

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