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