Atsuko Kita (1), Kiyomi Imano (1), Yasuhiro Seto (1), Ikuhisa Yakuo (2),
Takashi Deguchi (3) and Hideo Nakamura (4)
(1) Department of Pharmacology I, Discovery Research Laboratories I,
(2) Department of Toxicology and Pharmacology, Developmental Research
Laboratories, (3) Department of Chemistry II, Discovery Research Laboratories
II and (4) Division of Drug Regulatory Affairs, Dainippon Pharmaceutical
Co., Ltd., 33-94 Enoki, Suita/Osaka 564, Japan
Abstract: 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.
Keywords: BL-2401, Enkephalinase inhibitor, Antinociception, Antidepressant-like
action, Opioid