A Review of the Therapeutic Potential of Recently Developed G Protein-Biased Kappa Agonists

Abstract

Between 2000 and 2005 several studies revealed that morphine is more potent and exhibits fewer side effects in beta-arrestin 2 knockout mice. These findings spurred efforts to develop opioids that signal primarily via G protein activation and do not, or only very weakly, recruit beta-arrestin. Development of such molecules targeting the mu opioid receptor initially outpaced those targeting the kappa, delta and nociceptin opioid receptors, with the G protein-biased mu opioid agonist oliceridine/TRV130 having completed phase III clinical trials with improved therapeutic window to treat moderate-to-severe acute pain. Recently however, there has been a sharp increase in the development of novel G protein-biased kappa agonists. It is hypothesized that G protein-biased kappa agonists can reduce pain and itch, but exhibit fewer side effects, such as anhedonia and psychosis, that have thus far limited the clinical development of unbiased kappa opioid agonists. Here we summarize recently discovered G protein-biased kappa agonists, comparing structures, degree of signal bias and preclinical effects. We specifically reviewed nalfurafine, 22-thiocyanatosalvinorin A (RB-64), mesyl-salvinorin B, 2-(4-(furan-2-ylmethyl)-5-((4-methyl-3-(trifluoromethyl)benzyl)thio)-4H-1,2,4-triazol-3-yl)pyridine (triazole 1.1), 3-(2-((cyclopropylmethyl)(phenethyl)amino)ethyl)phenol (HS666), N-n -butyl- N -phenylethyl- N -3-hydroxyphenylethyl-amine (compound 5/BPHA), 6-guanidinonaltrindole (6′GNTI), and collybolide. These agonists encompass a variety of chemical scaffolds and range in both their potency and efficacy in terms of G protein signaling and beta-arrestin recruitment. Thus unsurprisingly, the behavioral responses reported for these agonists are not uniform. Yet, it is our conclusion that the kappa opioid field will benefit tremendously from future studies that compare several biased agonists and correlate the degree of signaling bias to a particular pharmacological response.

Evaluation of Biased and Balanced Salvinorin A Analogs in Preclinical Models of Pain

“…agonists (DiMattio et al, 2015;White et al, 2015;Dunn et al, 2018Dunn et al, , 2019Ho et al, 2018;Kaski et al, 2019;Mores et al, 2019). In addition, a recent paper showed low intrinsic efficacy, rather than G-protein bias, could explain the reduced respiratory side effects in MOPr agonists (Gillis et al, 2020).…”

Functional Selectivity and Antinociceptive Effects of a Novel KOPr Agonist

“…Oliceridine is one of the first MOPr G protein pathway-selective modulators that had undergone phase-IIb clinical trials for the management of moderate to severe acute pain following abdominoplasty (Singla et al, 2017); after that, Oliceridine completed also Phase III clinical trials, but in October 2018 the US FDA decided not to approve it, due to doubts whether the benefits associated with the drug outweighed the risks (Mores et al, 2019). This decision significantly dampened the enthusiasm around biased agonists at opioid receptors (especially at MOPr) as potential improved analgesics.…”

“…However, FDA decision was taken with 8 votes for rejection and 7 votes for approval; thus highlighting once more that the potential utility of biased agonists at opioid receptors is still highly debated and cannot be completely ruled out at the moment; thus, suggesting that further studies are necessary to fully understand if and how it will be possible to develop novel opioid analgesics more effective and safer than morphine by exploiting functional selectivity at opioid receptors. Moreover, although biased agonism at MOPr has been so far disappointing in terms of getting novel therapeutics into the market, functional selectivity at KOPr is still considered interesting and potentially promising: it is believed, in fact, that the whole kappa opioid field will greatly benefit from future studies aimed at analyzing novel compounds on one hand, and at correlating the degree of signaling bias to particular pharmacological responses on the other (Mores et al, 2019). Within this perspective, we believe that our findings on LOR17 may represent a significant advance.…”

“…As regard functional selective opioid ligands it is important to remind that in October 2018, the US FDA did not approve the Gprotein biased MOPr agonist oliceridine, as it was found not safer than morphine (Azzam et al, 2019); nonetheless, great interest in developing biased ligands at other GPCRs as KOPr still remains (Conibear and Kelly, 2019), and future studies analyzing novel compounds and correlating the degree of signaling bias to specific pharmacological responses are considered greatly beneficial for the whole kappa field (Mores et al, 2019).…”

Strategies for DevelopingκOpioid Receptor Agonists for the Treatment of Pain with Fewer Side Effects

“…For instance, in mice lacking GRK3, aversion is absent (Bruchas et al, 2007). Therefore, developing biased KOPr agonists, with preferential activation of the G-protein pathway, has received significant attention (reviewed by Mores et al (2019)). Biased agonism is calculated by evaluating activation in both G-protein and βarrestin signalling pathways and comparing affinity and efficacy to a reference agonist with balanced signalling properties.…”