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

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 (IC ₅₀  = 0.029 μM) versus MOR (IC ₅₀  = 3.3 μM) and DOR (IC ₅₀  > 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 (EC ₅₀  > 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.
Competing Interests: Declaration of competing interest Filomene G. Morrison, Lori Jean Van Orden, Karla Zeitz, and Tanya L. Wallace are employees of Neumora Therapeutics, Inc. (which acquired BlackThorn Therapeutics, Inc.) and have ownership interest (stock, stock options, royalty, receipt of intellectual property rights/patent holder, excluding diversified mutual funds) in Neumora Therapeutics, Inc. Sharon L. Smith and David J. Heal are shareholders and employees of DevelRx Ltd which is a consultancy company that advises the pharmaceutical industry on the discovery and development of central nervous system drugs. Eloise J. Kuijer has no declaration of competing interests. The opinions expressed in this manuscript are exclusively those of the authors and have not been influenced by any public, commercial, or not-for-profit organization.
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