Kappa opioid receptor agonist

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... 

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. 

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. 

Abrahamsson C (2000) Neuropeptide Y1- and Y2-receptor-mediated cardiovascular effects in the anaesthetized guinea pig, rat, and rabbit. J Cardiovasc Pharmacol 36 451-8 Ackley MA, Hurley RW, Virnich DE et al (2001) A cellular mechanism for the antinociceptive effect of a kappa opioid receptor agonist. Pain 91 377-88 Aimone LD, Yaksh TL (1989) Opioid modulation of capsaicin-evoked release of substance P from rat spinal cord in vivo. Peptides 10 1127-31... 

Schlosser B, Kudernatsch MB, Sutor B et al (1995) Delta, mu and kappa opioid receptor agonists inhibit dopamine overflow in rat neostriatal slices. Neurosci Lett 191 126-30 Schwertfeger E, Klein T, Vonend O et al (2004) Neuropeptide Y inhibits acetylcholine release in human heart atrium by activation of Y2-receptors. Naunyn-Schmiedeberg s Arch Pharmacol... 

Randic, M., Cheng, G., and Kojic, L. (1995). Kappa-opioid receptor agonists modulate excitatory transmission in substantia gelatinosa neurons of the rat spinal cord. J. Neurosci. 15, 6809-6826. Ransom, R. W., and Stec, N. L. (1988). Cooperative modulation of [3H] MK-801 binding to the jV-methyl-D-aspartate receptor-ion channel complex by L-glutamate, glycine, and polyamines. 

Fig. 11.17 Structure of the non-nitrogenous kappa opioid receptor agonist, salvinorin A.

Siebert, D. J., et al. (2004). Salvinorum A, an active component of the hallucinogenic sage Salvia divinorum is a highly efficacious kappa-opioid receptor agonist Structural and functional considerations. The Journal of Pharmacolojfy and Ecperimetital Therapeuties, 508, 1197-1203. 

Ness T J 1999 Kappa opioid receptor agonists differentially inhibit two classes of rat spinal neurons excited by colorectal distention. Gastroenterology 117 388-394 Nguyen A, Camilleri M, Kost L J et al 1997 SDZ HTF 919 stimulates canine colonic motility and transit in vivo. Journal of Pharmacology and Experimental Therapeutics 280 1270-1276... 

Mori T, Nomura M, Nagase H, Narita M, Suzuki T (2002) Effects of a newly synthesized kappa-opioid receptor agonist, TRK-820, on the discriminative stimulus and rewarding effects of cocaine in rats. Psychopharmacol 161 17-22... 

Scheerer JR, Lawrence JF, Wang GC et al (2007) Asymmetric synthesis of salvinorin A, a potent kappa opioid receptor agonist. J Am Chem Soc 129 8968-8969... 

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... 

Kane BE, Nieto MJ, McCurdy CR, Ferguson DM (2006) A unique binding epitope for salvinorin A, a non-nitrogenous kappa opioid receptor agonist. FEBS J 273 1966-1974... 

Yamaotsu N, Fujii H, Nagase H, Hirono S (2010) Identification of the three-dimensional pharmacophore of kappa -opioid receptor agonists. Bioorg Med Chem 18 4446-4452... 

Potential of Kappa Opioid Receptor Agonists To Produce Immunomodulation... 

A complimentary approach to the commonly found 0-alkylated major products in pyridone alkylations was found by Semple and coworkers in their preparation of Kappa Opioid receptor agonists. In their hands, TBP and TMAD gave moderate to good yields of A-alkylated pyridone derivatives (260) as shown below. A solid supported variant of this reaction, in which the alcohol moiety was tethered to the solid support, was developed as well. 

The tricyclic diterpene salvinorin A (14) is a trans-clerodane diterpenoid isolated from the Mexican plant Salvia divinorum. It acts as a kappa opioid receptor agonist and it is the first non-aUcaloid compound acting on this receptor [27]. Salvinorin A is the most potent hallucinogen isolated from plants and it is also capable of inhibiting excess intestinal motility (e.g., diarrhea), through a combination of k-opioid and cannabinoid receptors. 

A.W. Thomas, M. Kavaliers, F.S. Prato, et al. Pulsed magnetic field induced analgesia in the land snail, Cepaeanemoralis, and the effects of mu, delta, and kappa opioid receptor agonists/antagonists Peptides 1997, vol. 18, pp. 703-709. 

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