DOR positive allosteric modulator BMS-986187 attenuates depression and pain without convulsions

The delta opioid receptor (DOR) is a promising target for treating depression and certain pain disorders. However, direct DOR agonists have faced challenges in clinical translation due to their propensity to cause convulsions at higher doses, limiting their therapeutic window. The discovery of allosteric modulation for DOR offers a novel strategy to achieve therapeutic benefits, either by enhancing endogenous opioid peptides or by allowing lower, safer doses of DOR agonists, thereby potentially mitigating convulsive side effects.

Researchers investigated the behavioral effects of BMS-986187, a positive allosteric modulator of the DOR, in an animal model. They examined its antidepressant-like effects in the forced swim test when administered alone at 1 mg/kg. The study also assessed its antinociceptive and antiallodynic actions, as well as its propensity to cause convulsions, both alone and in combination with the standard DOR agonist SNC80. For combination studies, BMS-986187 (10 mg/kg) was co-administered with SNC80.

BMS-986187 demonstrated significant therapeutic potential across multiple behavioral endpoints. When administered alone, BMS-986187 (1 mg/kg) showed clear antidepressant-like effects in the forced swim test. Crucially, this dose of BMS-986187 did not produce convulsions, addressing a major limitation of direct DOR agonists. In combination experiments, BMS-986187 (10 mg/kg) enhanced the antinociceptive and antiallodynic effects of the standard DOR agonist SNC80. This synergistic effect suggests a dose-sparing potential for DOR agonists. Importantly, the combination of BMS-986187 with SNC80 resulted in only a very minor effect on SNC80-mediated convulsions, indicating a favorable safety profile.

The positive allosteric modulator BMS-986187 (1 mg/kg) alone showed antidepressant-like effects and did not produce convulsions.