Antinociceptive and antidepressant-like profiles of BL-2401, a novel enkephalinase inhibitor, in mice and rats.

To clarify the properties of BL-2401 ((+/-)-3-[2-benzyl-3-(propionylthio) propionyl]amino-5-methylbenzoic acid), a novel enkephalinase inhibitor, we examined its antinociceptive and antidepressant-like activities after oral administration, along with their association with endogenous opioid systems. BL-2401 produced an antinociceptive effect after oral administration in the mouse phenylbenzoquinone writhing test (ED50: 12.4 mg/kg) and the rat acetic acid writhing test (ED50: 55.8 mg/kg), the antinociceptive effect being antagonized by naloxone hydrochloride. BL-2401 also relieved arthritis-induced hyperalgesia in rats. In the mouse hot-plate and tail pressure tests, BL-2401 showed significant but modest antinociception at higher doses (200 and 400 mg/kg). In addition, BL-2401 (100 mg/kg) produced a naloxone-reversible antidepressant-like effect in the mouse forced swimming test. As for the mechanism of the action, the active metabolite of BL-2401, BL-2240 ((+/-)-3-(2-benzyl-3-mercaptopropionyl) amino-5-methylbenzoic acid), selectively inhibited enkephalinase in vitro (IC50: 5.2 nM). Oral administration of BL-2401 to mice significantly inhibited the enkephalinase activity in the striatum and also potentiated the antinociceptive effect of (D-Ala2,Met5)-enkephalin given intracisternally. These findings indicate that BL-2401 is an orally active enkephalinase inhibitor and may produce antinociceptive and antidepressant-like effects in association with endogenous opioid systems.