Antinociceptive and antidepressant-like profiles of BL-2401, a novel enkephalinase inhibitor, in mice and rats.

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.

• Authors: A Kita, K Imano, Y Seto, I Yakuo, T Deguchi, H Nakamura
• Journal: Japanese journal of pharmacology (Jpn J Pharmacol) Vol. 75 Issue 4 Pg. 337-46 (Dec 1997) ISSN: 0021-5198 [Print] Japan
• PMID: 9469639 (Publication Type: Journal Article)

Chemical References

• 3-(2-benzyl-3-(propionylthio)propionyl)amino-5-methybenzoic acid
• 3-(2-benzyl-3-mercaptopropionyl) amino-5-methylbenzoic acid
• Analgesics
• Analgesics, Opioid
• Antidepressive Agents
• Benzoates
• Benzoquinones
• Narcotic Antagonists
• Narcotics
• Sulfhydryl Compounds
• cassumunin A
• phenylbenzoquinone
• Naloxone
• Enkephalin, Methionine
• enkephalin-Met, Ala(2)-
• Neprilysin
• Curcumin

Topics

• Administration, Oral
• Analgesics (administration & dosage, pharmacology)
• Analgesics, Opioid (pharmacology)
• Animals
• Antidepressive Agents (administration & dosage, pharmacology)
• Benzoates (administration & dosage, pharmacology)
• Benzoquinones
• Corpus Striatum (drug effects, enzymology)
• Curcumin (analogs & derivatives, isolation & purification, pharmacology)
• Dose-Response Relationship, Drug
• Drug Synergism
• Enkephalin, Methionine (analogs & derivatives, pharmacology)
• Female
• Hyperalgesia (chemically induced, drug therapy)
• Male
• Mice
• Naloxone (pharmacology)
• Narcotic Antagonists (pharmacology)
• Narcotics (metabolism)
• Neprilysin (antagonists & inhibitors)
• Pain (chemically induced, drug therapy)
• Pain Measurement
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar
• Sulfhydryl Compounds (administration & dosage, pharmacology)
• Swimming