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

• Published in: Japanese Journal of Pharmacology 1997, Vol.75(4), pp.337-346
• Main Authors: Kita, Atsuko, Imano, Kiyomi, Seto, Yasuhiro, Yakuo, Ikuhisa, Deguchi, Takashi, Nakamura, Hideo
• Format: Article
• Language: English
• Subjects: Administration, Oral; Analgesics - administration & dosage; Analgesics - pharmacology; Analgesics, Opioid - pharmacology; Animals; Antidepressant-like action; Antidepressive Agents - administration & dosage; Antidepressive Agents - pharmacology; Antinociception; Benzoates - administration & dosage; Benzoates - pharmacology; Benzoquinones; BL-2401; Corpus Striatum - drug effects; Corpus Striatum - enzymology; Curcumin - analogs & derivatives; Curcumin - isolation & purification; Curcumin - pharmacology; Dose-Response Relationship, Drug; Drug Synergism; Enkephalin, Methionine - analogs & derivatives; Enkephalin, Methionine - pharmacology; Enkephalinase inhibitor; Female; Hyperalgesia - chemically induced; Hyperalgesia - drug therapy; Male; Mice; Naloxone - pharmacology; Narcotic Antagonists - pharmacology; Narcotics - metabolism; Neprilysin - antagonists & inhibitors; Opioid; Pain - chemically induced; Pain - drug therapy; Pain Measurement; Rats; Rats, Sprague-Dawley; Rats, Wistar; Sulfhydryl Compounds - administration & dosage; Sulfhydryl Compounds - pharmacology; Swimming
• ISSN: 0021-5198; 1347-3506
• DOI: 10.1254/jjp.75.337

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: 12.4mg/kg) and the rat acetic acid writhing test (ED50: 55.8mg/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.