Identification of Novel Functionally Selective κ-Opioid Receptor Scaffolds

Abstract

The k-opioid receptor (KOR)-dynorphin system has been implicated in the control of affect, cognition, and motivation, and is thought to be dysregulated in mood and psychotic disorders, as well as in various phases of opioid dependence. KOR agonists exhibit analgesic effects, although the adverse effects produced by some KOR agonists, including sedation, dysphoria, and hallucinations, have limited their clinical use. Interestingly, KOR-mediated dysphoria, assessed in rodents as aversion, has recently been attributed to the activation of the p38 mitogen-activated protein kinase pathway following arrestin recruitment to the activated KOR. Therefore, KOR-selective G protein-biased agonists, which do not recruit arrestin, have been proposed to be more effective analgesics, without the adverse effects triggered by the arrestin pathway. As an initial step toward identifying novel biased KOR agonists, we applied a multifaceted screening strategy utilizing both in silico and parallel screening approaches. We identified several KORselective ligand scaffolds with a range of signaling bias in vitro. The arylacetamide-based scaffold includes both G protein-and b-arrestin-biased ligands, while the endogenous peptides and the diterpene scaffolds are G protein biased. Interestingly, we found scaffold screening to be more successful than library screening in identifying biased ligands. Many of the identified functionally selective ligands are potent selective KOR agonists that are reported to be active in the central nervous system. They therefore represent excellent candidates for in vivo studies aiming at determining the behavioral effects mediated by specific KORmediated signaling cascades.

Collybolide is a novel biased agonist of κ-opioid receptors with potent antipruritic activity

“…Such studies are particularly important given reports that biased signaling at κOR can distinguish the aversive effects of κOR agonists from the antinociceptive effects (8). Consistent with this, studies have shown that, whereas Sal A appears to be an unbiased ligand based on G-protein activation and β-arrestin recruitment assays, a structural derivative, RB-64, appears to exhibit G-protein-biased activity (32). Studies with this compound argue for a contribution of the G-protein pathway in κOR-mediated analgesia and aversion and of other pathways on κOR-mediated motor coordination, sedation, and anhedonia (33).…”

Functional Selectivity of Kappa Opioid Receptor Agonists in Peripheral Sensory Neurons

“…Several reports have demonstrated KOR ligand functional selectivity in HEK cells Rives et al, 2012;Schattauer et al, 2012;White et al, 2014White et al, , 2015 and immortalized astrocytes (McLennan et al, 2008), and it has been suggested that ligands biased for G protein activation may be more effective analgesics (Bruchas et al, 2007a;White et al, 2015). Although well established in heterologous expression systems, there are relatively few studies that have established the functional selectivity of ligands toward cellular signaling pathways in physiologically relevant systems (Bailey et al, 2009;Melief et al, 2010;Schmid and Bohn, 2010;Bosier et al, 2012;Morgan et al, 2014;White et al, 2015).…”

Fulfilling the Promise of "Biased" G Protein–Coupled Receptor Agonism

“…However, their clinical utility is hampered by an array of undesirable side effects, including dysphoria, sedation, diuresis, hallucination, and depression (Pfeiffer et al, 1986;Togashi et al, 2002;Land et al, 2008;Van't Veer and Carlezon, 2013). Interestingly, it has been proposed that the dysphoric component of KOR agonism is mediated via a process involving arrestins (Bruchas et al, 2006;Redila and Chavkin, 2008), suggesting that G protein biased KOR agonists may deliver the desired analgesic effect while circumventing deleterious mood disturbances Zhou et al, 2013;White et al, 2014).…”