The novel δ opioid receptor agonist KNT-127 produces antidepressant-like and antinociceptive effects in mice without producing convulsions

We previously reported that the δ opioid receptor (DOP) agonists SNC80 and TAN-67 produce potent antidepressant-like and antinociceptive effects in rodents. However, SNC80 produced convulsive effects. Recently, we succeeded in synthesizing a novel DOP agonist called KNT-127. The present study examined the convulsive, antidepressant-like, and antinociceptive effects of KNT-127 in mice. In contrast to SNC80, KNT-127 produced no convulsions at doses of up to 100 mg/kg. In mice subjected to the forced swim test, a screening model for antidepressants, KNT-127 (1 mg/kg, s.c.) significantly decreased the duration of immobility and increased the duration of swimming without influencing spontaneous locomotor activity. These behavioral changes were similar to that observed for the tricyclic antidepressant imipramine (6 mg/kg). The antidepressant-like effect of KNT-127 in mice was antagonized by pretreatment with naltrindole (NTI), a selective DOP antagonist, or naltriben, a putative DOP2 subtype antagonist. In addition, KNT-127 (3 mg/kg, s.c.) significantly reduced the number of acetic acid-induced abdominal constrictions and the duration of licking time, respectively, in mice subjected to a writhing test and a formalin test. These antinociceptive effects were antagonized by pretreatment with either NTI or 7-benzylidenenaltrexone, a putative DOP1 subtype antagonist. We propose that KNT-127 should be considered as a candidate compound for the development of DOP-based antidepressants and/or analgesics that lack convulsive effects.

► A novel δ opioid receptor (DOP) agonist KNT-127 produced no convulsions in mice. ► KNT-127 produced antidepressant-like effects in mice forced swim test. ► KNT-127 produced antinociceptive effects in mice writhing and/or formalin tests. ► These pharmacological effects were completely reversed by NTI, DOP antagonist.