Antinociceptive and Antidepressant-Like Profiles of BL-2401, a Novel Enkephalinase Inhibitor, in Mice and Rats

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    • Kita Atsuko KITA Atsuko
    • Department of Pharmacology I, Discovery Research Laboaratories I, Dainippon Pharmaceutical Co., Ltd.
    • YAKUO Ikuhisa
    • Department of Toxicology and Pharmacology, Developmental Research Laboratories, Dainippon Pharmaceutical Co., Ltd.
    • DEGUCHI Takashi
    • Department of Chemistry II, Discovery Research Laboratories II, Dainippon Pharmaceutical Co., Ltd.
    • NAKAMURA Hideo
    • Division of Drug Regulatory Affairs, Dainippon Pharmaceutical Co., Ltd.


To clarify the properties of BL-2401 ((±)-3-[2-benzyl-3-(propionylthio) propionyl]amino-5methylbenzoic acid), a novel enkephalinase inhibitor, we examined its antinociceptive and antidepressantlike activities after oral administration, along with their association with endogenous opioid systems. BL2401 produced an antinociceptive effect after oral administration in the mouse phenylbenzoquinone writhing test (ED<SUB>50</SUB>: 12.4 mg/kg) and the rat acetic acid writhing test (ED<SUB>50</SUB>: 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 (IC<SUB>50</SUB>: 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-A1aSUP>2</SUP>, Met<SUP>5</SUP>)-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.


  • The Japanese Journal of Pharmacology

    The Japanese Journal of Pharmacology 75(4), 337-346, 1997-12-01

    The Japanese Pharmacological Society

References:  35

Cited by:  2


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