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.

Highlights

  • Specialty section: This article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology

  • 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 far limited the clinical development of unbiased kappa opioid agonists

  • The beginning of the 21st century saw the emergence of the hypothesis that the side effect profile of μ opioid receptor (μOR) based drugs may be attributed to β-arrestin 2 signaling, as preclinical studies showed that mice lacking this protein displayed reduced morphine tolerance and respiratory depression (Bohn et al, 1999, 2000; Raehal et al, 2005)

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Summary

METHODOLOGY AND LIMITATIONS OF MEASURING BIASED SIGNALING IN VITRO

The cellular environment strongly impacts the efficacy with which an agonist can engage a signal transduction pathway. For the κOR agonists discussed here, the predominant assay for G protein signaling utilized [35S]GTPγS, whereas β-arrestin recruitment was primarily assessed using the proprietary PathHunter cells from DiscoverX. A 2014 study showed similarities and differences in potency and efficacy for κOR agonists when assessed in the TANGO or BRET assay, with the primary difference that partial agonism was more apparent in the TANGO assay. This is not a rule, as partial agonism of β-arrestin recruitment at dopamine D2 receptor was more apparent using the PathHunter and BRET assay than using the TANGO assay (Allen et al, 2011)

CALCULATIONS OF BIAS
Depression References
Anhedonia Anxiety Depression References
Findings
CONCLUSION AND FUTURE DIRECTIONS
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