STRUCTURAL FEATURES RESULTING IN CONVULSIVE ACTIVITY OF CARBAPENEM COMPOUNDS - EFFECT OF C-2 SIDE-CHAIN

The neurotoxicity of meropenem was much lower than that of both imipen em and panipenem after intraventricular administration to mice. To cla rify the major structural features responsible for the induction of co nvulsions by carbapenem antibiotics, the structure-activity relationsh ip on convulsant activity was investigated in N-acetyl-2-pyrroline and cyclopentene derivatives which correspond to the 5-membered ring cont aining the C-2 side chain of carbapenem antibiotics. Among these deriv atives, compounds with strong basicity in the side chain showed convul sant activity similar to that of the parent carbapenem compounds. In a ddition to the strength of the basicity of the amino group, the distan ce 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 (GABA(A)) recep tor binding assays indicated that the induction of convulsions was cau sed predominantly by the inhibition of GABA(A)-mediated inhibitory tra nsmission. However, the in vivo convulsant activity of some of these c ompounds did not correlate with their in vitro inhibitory effect on GA BA(A) receptor binding.