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

Abstract

The neurotoxicity of meropenemwas muchlower than that of both imipenemand panipenem after intraventricular administration to mice. To clarify the majorstructural features responsible for the induction of convulsions by carbapenemantibiotics, the structure-activity relationship on convulsant activity was investigated in iV-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, compoundswith 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 gammaaminobutyric acid (GABAA) receptor binding assays indicated that the induction of convulsions was caused predominantly by the inhibition of GABAA-mediatedinhibitory transmission. However, the in vivo convulsant activity of some of these compoundsdid not correlate with their in vitro inhibitory effect on GABAA receptor binding.

Pharmacokinetic-Pharmacodynamic Modeling of the Electroencephalogram Effect of Imipenem in Healthy Rats

“…Among these, an active metabolite accumulating with time could contribute to the observed EEG effect. Several authors have suggested that the convulsant activity of imipenem was related to the accumulation of an open lactam metabolite (18,37), but other results suggest that the parent compound itself would be responsible for the neurotoxicity (29,36). However, this metabolite is not detected in serum and cannot be included in a PK-PD model.…”

Novel Carbapenem Antibiotics for Parenteral and Oral Applications: In Vitro and In Vivo Activities of 2-Aryl Carbapenems and Their Pharmacokinetics in Laboratory Animals

“…The convulsant stability of carbapenems was determined as reported previously (17). Seven-week-old male ICR mice were intracerebroventricularly injected with each dose (50 to 400 g/mouse) of drugs dissolved in 5 l phosphate-buffered saline.…”

New Anti-MRSA and Anti-VRE Carbapenems; Synthesis and Structure-activity Relationships of 1.BETA.-Metyl-2-(thiazol-2-ylthio)carbapenems.

“…Furthermore the introduction of a double bond-conjugated to the thiazole ring-into the piperidine/pyrrolidine ring (23 and 27), which influences both the position of the cationic center, and the basicity, due to inductive effects, showed no significant effects on the anti-VREFm activity. Finally the effect of introduction of N-substituents (30)(31)(32)(33)(34)(35)(36)(37)(38)(39) on the anti-VREFm activity is slight and smaller than that on the anti-MRSA activity.…”

“…The product was purified by chromatography on MCI gel (CHP-20P) to give 31: IR (KBr) cm -1 3401, 1764, 1710, 1596 -methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic Acid (32) To a solution of 23 (85mg, 0.21mmol) (33) To a solution of C30 (830mg, 1.5mmol) in EtOAc (16ml) was added iodoacetamide (550mg, 3.0mmol) at room temperature. After stirring for 30 minutes, the precipitate was separated by decantation and dried in vacuo.…”