Acute toxicity induced by 2-aryl-N-methylsuccinimides

Area of Science:

• Pharmacology
• Toxicology
• Medicinal Chemistry

Background:

• Phensuximide (PSX), a 2-arylsuccinimide, is used to treat absence seizures and is a mild urotoxicant.
• Structural analogs of N-phenylsuccinimide (NPS) with chloro or tert-butyl substitutions exhibit enhanced nephrotoxicity.
• This study investigates if similar substitutions on PSX enhance its nephrotoxic potential.

Purpose of the Study:

• To synthesize and evaluate three PSX derivatives: 2-(3-chlorophenyl)-N-methylsuccinimide (CPMS), 2-(4-tert-butylphenyl)-N-methylsuccinimide (BPMS), and 2-(3,5-dichlorophenyl)-N-methylsuccinimide (DPMS).
• To assess the nephrotoxic and urotoxic potential of these derivatives in male Fischer 344 rats.
• To determine the effect of phenobarbital pretreatment on the toxicity of DPMS.

Main Methods:

• Rats received single intraperitoneal injections of PSX derivatives (0.4 or 1.0 mmol kg-1) or vehicle.
• Renal function was monitored at 24 and 48 hours post-injection.
• A subset of rats underwent phenobarbital pretreatment before DPMS administration to evaluate combined toxicity.

Main Results:

• PSX derivatives induced only minor changes in renal function; BPMS and DPMS at 1.0 mmol kg-1 caused mild renal tubular necrosis and glomerular membrane thickening.
• Phenobarbital pretreatment did not significantly enhance DPMS nephrotoxicity at 0.4 mmol kg-1 but increased tubular necrosis at 1.0 mmol kg-1.
• Combined phenobarbital and high-dose DPMS treatment resulted in significant hepatotoxicity, mortality, proteinuria, hematuria, and extensive kidney damage.

Conclusions:

• Unlike NPS analogs, chemical substitutions on PSX did not significantly enhance nephrotoxic potential.
• DPMS can induce urotoxicity, similar to PSX, likely through its metabolites.
• Phenobarbital pretreatment exacerbates DPMS-induced toxicity, leading to severe organ damage and lethality.