Antinociceptive and antidepressant-like profiles of BL-2401, a novel
enkephalinase inhibitor, in mice and rats
by
Kita A, Imano K, Seto Y, Yakuo I, Deguchi T, Nakamura H
Department of Pharmacology I,
Dainippon Pharmaceutical Co., Ltd.,
Suita/Osaka, Japan.
Welsh School of Pharmacy,
University of Wales, Cardiff, U.K.
Jpn J Pharmacol 1997 Dec; 75(4):337-46
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.
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