Structurally Related Kappa Opioid Receptor Agonists with Substantial Differential Signaling Bias: Neuroendocrine and Behavioral Effects in C57BL6 Mice

Abstract

BackgroundThe kappa opioid receptor system has been revealed as a potential pharmacotherapeutic target for the treatment of addictions to substances of abuse. Kappa opioid receptor agonists have been shown to block the rewarding and dopamine-releasing effects of psychostimulants. Recent investigations have profiled the in vivo effects of compounds biased towards G-protein-mediated signaling, with less potent arrestin-mediated signaling. The compounds studied here derive from a series of trialkylamines: N-substituted-N- phenylethyl-N-3-hydroxyphenylethyl-amine, with N-substituents including n-butyl (BPHA), methylcyclobutyl (MCBPHA), and methylcyclopentyl (MCPPHA).MethodsBPHA, MCBPHA, and MCPPHA were characterized in vitro in a kappa opioid receptor-expressing cell line in binding assays and functional assays. We also tested the compounds in C57BL6 mice, assaying incoordination with rotarod, as well as circulating levels of the neuroendocrine kappa opioid receptor biomarker, prolactin.ResultsBPHA, MCBPHA, and MCPPHA showed full kappa opioid receptor agonism for G-protein coupling compared with the reference compound U69,593. BPHA showed no measurable β-arrestin-2 recruitment, indicating that it is extremely G-protein biased. MCBPHA and MCPPHA, however, showed submaximal efficacy for recruiting β-arrestin-2. Studies in C57BL6 mice reveal that all compounds stimulate release of prolactin, consistent with dependence on G-protein signaling. MCBPHA and MCPPHA result in rotarod incoordination, whereas BPHA does not, consistent with the reported requirement of intact kappa opioid receptor/β-arrestin-2 mediated coupling for kappa opioid receptor agonist-induced rotarod incoordination.ConclusionsBPHA, MCBPHA, and MCPPHA are thus novel differentially G-protein-biased kappa opioid receptor agonists. They can be used to investigate how signaling pathways mediate kappa opioid receptor effects in vitro and in vivo and to explore the effects of candidate kappa opioid receptor-targeted pharmacotherapeutics.

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

“…Surprisingly, RB-64 is aversive in the conditioned place preference paradigm, albeit it does not involve b-arrestin-2 recruitment at the kappa receptor (White et al, 2015); however, RB-64 did not increase anhedonia in rodents as compared to vehicle in the ICSS paradigm (White et al, 2015). Recently, three KOPr agonists provided with different degrees of functional selectivity toward G protein-dependent signaling were characterized with regard to their neuroendocrine and behavioral effects (Dunn et al, 2018): KOPrdependent sedative effects elicited by these ligands were symmetrical to their ability to recruit b-arrestin2 at KOPr. Thus, taken together, these data support the hypothesis that downstream of KOPr activation, sedation, coordination impairment and anhedonia may be due to b-arrestin-2 recruitment and aversion possibly related, at least in rodents, to arrestin-independent p38MAPK activation (White et al, 2015).…”

“…In this regard, an accumulating body of evidence suggests that KOPr agonists produce antinociception and anti-itch effects via G protein-mediated signaling (Bruchas and Chavkin, 2010;Morgenweck et al, 2015) while their b-arrestin-2-dependent induction of p38MAPK leads to many of the relevant adverse consequences, including centrally mediated dysphoria Ehrich et al, 2015), potassium channel heterologous desensitization (Clayton et al, 2009), neuropathy-induced astrocyte proliferation and related hyperalgesia , sedation, and motor incoordination (Dunn et al, 2018).…”

Nalbuphine Attenuates Microglial Activation and Inhibits Morphine-Induced Scratching via Regulation of PKCδ and p38 Signaling in Mice

“…Although the use of nalbuphine as a treatment for the pruritus associated with neuraxial opioid use has not been approved by the FDA, it has nevertheless been used in this capacity. In fact, one study found that nalbuphine was a better treatment for MIS than either a placebo, a control, diphenhydramine, naloxone, or propofol in patients receiving neuraxial opioids for acute pain related to surgery or childbirth [31]. However, the mechanism underlying nalbuphine's antipruritic effects is still unclear.…”