Kappa-Opioid Antagonists for Psychiatric Disorders: From Bench to Clinical Trials

Abstract

Kappa-opioid receptor (KOR) antagonists are currently being considered for the treatment of a variety of neuropsychiatric conditions, including depressive, anxiety, and substance abuse disorders. A general ability to mitigate the effects of stress, which can trigger or exacerbate these conditions, may explain their putative efficacy across such a broad array of conditions. The discovery of their potentially therapeutic effects evolved from preclinical research designed to characterize the molecular mechanisms by which experience causes neuroadaptations in the nucleus accumbens (NAc), a key element of brain reward circuitry. This research established that exposure to drugs of abuse or stress increases the activity of the transcription factor CREB (cAMP response element binding protein) in the NAc, which leads to elevated expression of the opioid peptide dynorphin, which in turn causes core signs of depressive- and anxiety-related disorders. Disruption of KORs—the endogenous receptors for dynorphin—produces antidepressant- and anxiolytic-like actions in screening procedures that identify standard drugs of these classes, and reduces stress effects in tests used to study addiction and stress-related disorders. Although interest in this target is high, prototypical KOR antagonists have extraordinarily persistent pharmacodynamic effects that complicate clinical trials. The development of shorter-acting KOR antagonists together with more rapid designs for clinical trials may soon provide insight on whether these drugs are efficacious as would be predicted by preclinical work. If successful, KOR antagonists would represent a unique example in psychiatry where the therapeutic mechanism of a drug class is understood before it is shown to be efficacious in humans.

Social defeat disrupts reward learning and potentiates striatal nociceptin/orphanin FQ mRNA in rats

“…Additionally, increased CREB expression in the NAc shell has been shown to increase brain stimulation reward thresholds in the intracranial self-stimulation procedure in rats (Muschamp et al 2011), similar to the effects of social defeat (Der-Avakian et al 2014; Donahue et al 2014). Conversely, environmental enrichment, which is associated with a reduction in depression-like behaviors, decreases CREB activity in the NAc (Green et al 2010), which produces antidepressant and antistress-like effects (Carlezon and Krystal 2016; Pliakas et al 2001). Altogether, the findings from our study are consistent with previously published data and suggest several molecular mechanisms that contribute to stress-related disruption of reward learning.…”

“…We hypothesized that social defeat would alter expression of stress- and MDD-related genes within key nodes implicated in reward learning. Owing to recent work implicating nociceptin and dynorphin systems in motivational states and depressive behaviors (Carlezon and Krystal 2016; Gavioli et al 2004; Post et al 2016), our primary analyses focused on them. For comparison, we also examined expression of a broad panel of genes (reflected by mRNA levels) that encode proteins implicated in neuronal function, plasticity, and inflammation.…”

What Is New about New Antidepressants?

“…Despite emerging data on the potential role of intracellular signals, gene expression, and network connectivity, many of these targets are still neurotransmitters and receptors. A few examples of such directions in antidepressant development are summarized in Table 2 [8, 23, 63, 64]. …”

Structure-Based Discovery of New Antagonist and Biased Agonist Chemotypes for the Kappa Opioid Receptor

“…20, 21 This study employed crystal structure-derived models of KOR 26 and a multi-template VLS approach to discover new fragment-like and lead-like chemotypes for KOR. The initial round of structure-based prospective VLS resulted in a high hit rate (32%) and the discovery of at least six novel KOR chemotypes, with best ligand affinity K i = 0.2 μM.…”

“…14–17 Although clinical development of JDTic was abandoned due to transient cardiovascular effects 18 and exceptionally long lasting action, 19 several other KOR selective antagonists are in various stages of clinical or preclinical studies. 20, 21 …”