Side effect reduction

The first kappa-agonists to be developed were brain-penetrating organic small molecules. Their development was eventually discontinued due to central side effects such as sedation and dysphoria attributed to kappa-receptors located behind the blood-brain barrier. New drug discovery programs are now geared towards the design of peripherally-selective kappa-agonists.¹ Peripherally selective opioids may be beneficial in visceral pain management due to absence of centrally mediated side effects.²

In one study, two novel, all d-amino acid, tetrapeptide kappa-opioid receptor agonists, FE 200665 and FE 200666, were identified and compared to brain penetrating (enadoline) and peripherally selective (asimadoline) kappa-agonists as potential analgesics lacking unwanted central nervous system (CNS) side effects. ). Markedly higher doses of FE 200665 and FE 200666 were required to induce centrally-mediated effects in the rotarod assay (548- and 182-fold higher doses, respectively), and antinociception determined in the mouse tail-flick assay.³

Several laboratories have produced a body of work suggesting that G protein-biased KOR agonists might be analgesic with fewer side effects. Data using a G protein-biased agonist, RB-64 (22-thiocyanatosalvinorin A), suggests that KOR-mediated G protein signaling induces analgesia and aversion, whereas beta-arrestin-2 signaling may be associated with motor incoordination. Additionally, unlike unbiased KOR agonists, the G protein-biased ligand RB-64 does not induce sedation and does not have anhedonia-like actions, suggesting that a mechanism other than G protein signaling mediates these effects. These findings provide evidence for a highly selective and G protein-biased tool compound for which many, but not all, of the negative side effects of KOR agonists can be minimized by creating G protein-biased KOR agonists⁴

In a double-blind, placebo-controlled clinical study with patients undergoing laparoscopic hysterectomy, pre- and/or postoperative intravenous administration of the kappa-opioid receptor agonist (IV) CR845 produced a reduction in pain intensity as well as decreased postoperative nausea and vomiting (PONV).⁵ A subsequent clinical study showed a substantial reduction in PONV with IV CR845 compared with placebo, despite similar use of fentanyl, raising the possibility of a direct anti-nausea/anti-emetic effect of CR845.⁶

¹Medve RA et al. Analgesic efficacy of the peripheral kappa opioid agonist CR845 in laparoscopic hysterectomy. Presented at the American Academy of Pain Medicine’s 31st Annual Meeting, March 19-22, 2015, National Harbor, MD.
²Medve RA et al. Analgesic efficacy of the peripheral kappa opioid agonist CR845 in laparoscopic hysterectomy. Presented at the American Academy of Pain Medicine’s 31st Annual Meeting, March 19-22, 2015, National Harbor, MD.
³Riviere PJ. Peripheral kappa-opioid agonists for visceral pain. Br J Pharmacol 2004 April;141(8):1331-4.
⁴Arendt-Nielsen L, Olesen AE, Staahl C et al. Analgesic efficacy of peripheral kappa-opioid receptor agonist CR665 compared to oxycodone in a multi-modal, multi-tissue experimental human pain model: selective effect on visceral pain. Anesthesiology 2009 September;111(3):616-24.
⁵Vanderah TW, Largent-Milnes T, Lai J et al. Novel D-amino acid tetrapeptides produce potent antinociception by selectively acting at peripheral kappa-opioid receptors. Eur J Pharmacol 2008 March 31;583(1):62-72
⁶White KL, Robinson JE, Zhu H et al. The G protein-biased kappa-opioid receptor agonist RB-64 is analgesic with a unique spectrum of activities in vivo. J Pharmacol Exp Ther 2015 January;352(1):98-109.