Structural Features Resulting in Convulsive Activity of Carbapenem Compounds: Effect of C-2 Side Chain

Makoto Sunagawa, Haruki Matsumura, Yoshihiro Sumita, Hiroshi Nouda

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

The neurotoxicity of meropenem was much lower than that of both imipenem and panipenem after intraventricular administration to mice. To clarify the major structural features responsible for the induction of convulsions by carbapenem antibiotics, the structure-activity relationship on convulsant activity was investigated in N-acetyl-2-pyrroline and cyclopentene derivatives which correspond to the 5-membered ring containing the C-2 side chain of carbapenem antibiotics. Among these derivatives, compounds with strong basicity in the side chain showed convulsant activity similar to that of the parent carbapenem compounds. In addition to the strength of the basicity of the amino group, the distance from the carboxyl to the amino group and steric crowding around the amino group also appeared to play an important role in the induction of convulsions. The results of gamma aminobutyric acid (GABAa) receptor binding assays indicated that the induction of convulsions was caused predominantly by the inhibition of GABAa-mediated inhibitory transmission. However, the in vivo convulsant activity of some of these compounds did not correlate with their in vitro inhibitory effect on Gabaa receptor binding.

Original languageEnglish
Pages (from-to)408-416
Number of pages9
JournalThe Journal of Antibiotics
Volume48
Issue number5
DOIs
Publication statusPublished - Jan 1 1995

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

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