Fig. 3: Oxa-noribogaine is an atypical KOR agonist in vivo with no aversion and no pro-depression-like effects at efficacious analgesic doses.

a Oxa-iboga analogs induce potent analgesia in the mouse tail-flick test (male mice), comparable in potency and efficacy to the standard kappa agonist, U50,488. b Analgesia of oxa-noribogaine and epi-oxa-noribogaine (c) is KOR dependent as demonstrated in KOR knock-out mice (KOR-KO), compared to mu receptor knock-out (MOR-KO) and wild type (WT) mice (KOR-KO vs WT, P < 0.0001). d Oxa-noribogaine induces potent analgesia in female mice, primarily driven by KOR as demonstrated in e female KOR-KO mice compared to MOR-KO and WT. f Traces visualizing ambulatory distance traveled by WT mice in open field test (OF) show different effects by the isomers at equianalgesic doses. g Quantification of OF test (ED₈₀ doses) for oxa-noribogaine (5.4 mg/kg, both male and female) and epi-oxa-noribogaine (5.2 mg/kg), data are normalized to initial locomotion of vehicle group. h Sedation of epi-oxa-noribogaine (5.2 mg/kg, P < 0.0001) is KOR-driven as demonstrated by pre-treatment (P < 0.0001) by the selective KOR antagonist aticaprant (ATI, 0.1 mg/kg). Total locomotion over 60 min period is normalized to vehicle. i No pro-depressive-like effects were detected using the forced swim test after oxa-noribogaine administration (30 min post administration). Imipramine was used as a positive effect control (P = 0.0031). j Male and female mice do not develop a conditioned place preference or aversion (CPP/CPA) after administration of oxa-noribogaine (P = 0.4531, P = 0.5994, respectively), in contrast to cocaine (10 mg/kg: P = 0.0029 and 0.0013) and morphine (20 mg/kg: P = 0.0010 and 0.0153). k Pharmacokinetic distribution of oxa-noribogaine in mice plasma and brain tissue (10 mg/kg). All drugs were administered via subcutaneous (s.c.) route except for intraperitoneal (i.p.) route for CPP/CPA test. % MPE (percentage of maximum potential effect). Data are presented as mean ± SEM. Statistical tests used: Unpaired (h, i) and paired (j) t-test, two-tailed, One-way (i) and Two-way (g, j) ANOVA with Šidák multiple comparisons test, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Source data are provided in the Source Data file.