Navacaprant

Navacaprant (BTRX-335140, NMRA-140, CYM-53093) is a potent, highly selective, and reversible antagonist of the kappa opioid receptor (KOR) under clinical development for the treatment of major depressive disorder (MDD). The compound was discovered in collaboration between Scripps Research faculty members Hugh Rosen and Edward Roberts and was advanced through clinical development first by BlackThorn Therapeutics and subsequently by Neumora Therapeutics. Navacaprant blocks the KOR with an IC50 of 1.2 nanomolar in native ventral tegmental area dopamine neurons and 29 nanomolar in recombinant CHO-K1 cells, with approximately 300-fold selectivity over the mu opioid receptor and greater than 340-fold selectivity over the delta opioid receptor. The compound exhibits no detectable agonist activity at any opioid receptor subtype in vitro (EC50 greater than 10 micromolar) and no opioid agonist effects in vivo, including no alteration of extracellular dopamine in the nucleus accumbens at oral doses up to 100 mg/kg in rats. The pharmacological profile differentiates navacaprant from earlier KOR antagonists: unlike JDTic (which activates c-Jun N-terminal kinase and produced cardiac toxicity in humans), nor-binaltorphimine (which has an impractically long duration of action), and aticaprant (which partially blocks mu and delta opioid receptor responses in native tissue electrophysiology), navacaprant combines full KOR antagonism with rapid reversibility, clean selectivity, and no off-target opioid effects. In a Phase 1 program in healthy volunteers, navacaprant demonstrated favorable pharmacokinetics across single oral doses of 5 to 240 mg and multiple daily doses of 20 to 160 mg for 10 days, with good tolerability and no serious adverse events. A positron emission tomography receptor occupancy study confirmed brain KOR engagement, with a single 160 mg dose producing approximately 90 percent occupancy and pharmacokinetic-pharmacodynamic modeling projecting approximately 90 percent occupancy at steady state with 80 mg in the published literature. In a Phase 2a randomized, double-blind, placebo-controlled trial in 204 adults with MDD (Mathew et al. 2025), navacaprant 80 mg in the published literature for 8 weeks did not meet the primary endpoint in the full efficacy population (Hamilton Depression Rating Scale least-squares mean difference versus placebo of negative 1.7 points, p equals 0.121), but demonstrated statistically significant improvements in the moderate-to-severe MDD subgroup on both depressive symptoms and anhedonia as measured by the Snaith-Hamilton Pleasure Scale, with response rates of 45.5 percent versus 24.1 percent for placebo (number needed to treat equals 5) and remission rates of 26.1 percent versus 10.8 percent (number needed to treat equals 7). Fewer treatment-emergent adverse events occurred in the navacaprant group than in the placebo group, and no serious adverse events, weight gain, or sexual dysfunction were reported with navacaprant. In Phase 3, the KOASTAL-1 trial (n equals 383) failed to demonstrate separation from placebo on the Montgomery-Asberg Depression Rating Scale primary endpoint, with both treatment arms reporting identical 12.5-point reductions (p equals 0.993); exploratory subgroup analyses suggested a differential response in female participants. The KOASTAL-2 and KOASTAL-3 Phase 3 trials were paused for protocol modifications and are expected to report data in 2026. This monograph reviews the chemistry and structural pharmacology of navacaprant; the molecular pharmacology including receptor binding, selectivity, and electrophysiological characterization; the available pharmacokinetic data; the preclinical pharmacology in stress and cognitive models; the clinical evidence base including the Phase 2 and Phase 3 programs; sourcing and quality verification; handling considerations; stack interactions; adverse events; and a comparative assessment of five kappa opioid receptor candidates (aticaprant, buprenorphine-samidorphan, JDTic, nor-binaltorphimine, and PF-04455242) against navacaprant. The compound is investigational and is not approved by any regulatory authority. It is available as a research-grade preparation; investigators should obtain analytical confirmation of identity and purity on every lot.