Abstract
Among the opioid receptors, the kappa opioid receptor (KOR) has been gaining substantial attention as a promising molecular target for the treatment of numerous human disorders, including pain, pruritus, affective disorders (i.e., depression and anxiety), drug addiction, and neurological diseases (i.e., epilepsy). Particularly, the knowledge that activation of the KOR, opposite to the mu opioid receptor (MOR), does not produce euphoria or leads to respiratory depression or overdose, has stimulated the interest in discovering ligands targeting the KOR as novel pharmacotherapeutics. However, the KOR mediates the negative side effects of dysphoria/aversion, sedation, and psychotomimesis, with the therapeutic promise of biased agonism (i.e., selective activation of beneficial over deleterious signaling pathways) for designing safer KOR therapeutics without the liabilities of conventional KOR agonists. In this review, the development of new KOR ligands from the class of diphenethylamines is presented. Specifically, we describe the design strategies, synthesis, and pharmacological activities of differently substituted diphenethylamines, where structure–activity relationships have been extensively studied. Ligands with distinct profiles as potent and selective agonists, G protein-biased agonists, and selective antagonists, and their potential use as therapeutic agents (i.e., pain treatment) and research tools are described.
Highlights
Throughout human history, opioids have been used for medicinal and recreational practices to relieve pain, cough, and diarrhea, and to induce euphoria
This study proposed that the mammalian target of rapamycin signaling pathway may be involved in mediating aversion caused by kappa opioid receptor (KOR)
Potent and selective KOR ligands have been targeted since the discovery of multiple opioid
Summary
Throughout human history, opioids have been used for medicinal and recreational practices to relieve pain, cough, and diarrhea, and to induce euphoria. Differential modulation of the KOR using selective ligands targeting the receptor is regarded a viable strategy for developing therapies for human disorders where the endogenous kappa opioid system plays a central role. Activation of G protein-mediated pathways upon KOR activation is recognized to be responsible for the beneficial effects of analgesia and anti-itching, while β-arrestin recruitment and subsequent p38 phosphorylation KOR are considered to be involved in the negative side effects of dysphoria/aversion and sedation [54,55] These findings that independent signaling mechanisms can be linked to distinct physiological effects of the KOR and can be pharmacologically separated by biased KOR ligands offer nowadays new perspectives in the discovery of KOR-targeted therapeutics with less liability for undesirable side effects.
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