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

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  • Kita Atsuko
    Department of Pharmacology I, Discovery Research Laboratories I, Dainippon Pharmaceutical Co., Ltd.
  • Imano Kiyomi
    Department of Pharmacology I, Discovery Research Laboratories I, Dainippon Pharmaceutical Co., Ltd.
  • Seto Yasuhiro
    Department of Pharmacology I, Discovery Research Laboratories I, Dainippon Pharmaceutical Co., Ltd.
  • Yakuo Ikuhisa
    Department of Toxicology and Pharmacology, Developmental Research Laboratories, Dainippon Pharmaceutical Co.
  • 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.

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  • Antinociceptive and Antidepressant-Like

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Abstract

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 (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-A1aSUP>2</SUP>, 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.

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