Navacaprant, a novel and selective kappa opioid receptor antagonist, has no agonist properties implicated in opioid-related abuse

• Published in: Neuropharmacology Vol. 257; p. 110037
• Main Authors: Morrison, Filomene G., Van Orden, Lori Jean, Zeitz, Karla, Kuijer, Eloise J., Smith, Sharon L., Heal, David J., Wallace, Tanya L.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.10.2024
• Subjects: Analgesics, Opioid - pharmacology; Animals; CHO Cells; Cricetinae; Cricetulus; Dopamine - metabolism; Dose-Response Relationship, Drug; Humans; Male; Mice; Mice, Inbred C57BL; Narcotic Antagonists - pharmacology; Nucleus Accumbens - drug effects; Nucleus Accumbens - metabolism; Opioid-Related Disorders - drug therapy; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta - agonists; Receptors, Opioid, delta - antagonists & inhibitors; Receptors, Opioid, kappa - agonists; Receptors, Opioid, kappa - antagonists & inhibitors; Receptors, Opioid, mu - agonists; Receptors, Opioid, mu - antagonists & inhibitors
• ISSN: 0028-3908; 1873-7064; 1873-7064
• DOI: 10.1016/j.neuropharm.2024.110037

Kappa opioid receptors (KORs) are implicated in the pathophysiology of various psychiatric and neurological disorders creating interest in targeting the KOR system for therapeutic purposes. Accordingly, navacaprant (NMRA-140) is a potent, selective KOR antagonist being evaluated as a treatment for major depressive disorder. In the present report, we have extended the pharmacological characterization of navacaprant by further demonstrating its selective KOR antagonist properties and confirming its lack of agonist activity at KORs and related targets involved in opioid-related abuse. Using CHO–K1 cells expressing human KOR, mu (MOR), or delta (DOR) opioid receptors, navacaprant demonstrated selective antagonist properties at KOR (IC50 = 0.029 μM) versus MOR (IC50 = 3.3 μM) and DOR (IC50 > 10 μM) in vitro. In vivo, navacaprant (10–30 mg/kg, i.p.) dose-dependently abolished KOR-agonist induced analgesia in the mouse tail-flick assay. Additionally, navacaprant (10, 30 mg/kg, p.o.) significantly reduced KOR agonist–stimulated prolactin release in mice and rats, confirming KOR antagonism in vivo. Navacaprant showed no agonist activity at any opioid receptor subtype (EC50 > 10 μM) in vitro and exhibited no analgesic effect in the tail-flick assays at doses ≤100 mg/kg, p.o. thereby confirming a lack of opioid receptor agonist activity in vivo. Importantly, navacaprant did not alter extracellular dopamine concentrations in the nucleus accumbens shell of freely-moving rats following doses ≤100 mg/kg, p.o., whereas morphine (10, 20 mg/kg, i.p.) significantly increased dopamine levels. These results demonstrate that navacaprant is a KOR-selective antagonist with no pharmacological properties implicated in opioid-related abuse. •Navacaprant (NMRA-140) is a potent kappa opioid receptor antagonist in vitro and in vivo.•Navacaprant is more than 100-fold selective for kappa opioid receptors vs the mu and delta opioid receptor subtypes.•Navacaprant has no detectable agonist activity at any opioid receptor subtype.•Navacaprant neither enhances nor attenuates mesolimbic dopamine concentrations in the nucleus accumbens shell.•Navacaprant has no pharmacological properties associated with opioid-related abuse.