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-(propionylth io) propionyl]amino-5-methylbenzoic acid), a novel enkephalinase inhib itor, we examined its antinociceptive and antidepressant-like activiti es after oral administration, along with their association with endoge nous opioid systems. BL-2401 produced an antinociceptive effect after oral administration in the mouse phenylbenzoquinone writhing test (ED5 0: 12.4 mg/kg) and the rat acetic acid writhing test (ED50: 55.8 mg/kg ), the antinociceptive effect being antagonized by naloxone hydrochlor ide. BL-2401 also relieved arthritis-induced hyperalgesia in rats. In the mouse hot-plate and tail pressure tests, BL-2401 showed significan t but modest antinociception at higher doses (200 and 400 mg/kg). In a ddition, BL-2401 (100 mg/kg) produced a naloxone-reversible antidepres sant-like effect in the mouse forced swimming test. As for the mechani sm 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- Ala(2),Met(5))-enkephalin given intracisternally. These findings indic ate that BL-2401 is an orally active enkephalinase inhibitor and may p roduce antinociceptive and antidepressant-like effects in association with endogenous opioid systems.