PHARMACOLOGY OF CL-966 - A POTENT GABA UPTAKE INHIBITOR, INVITRO AND IN EXPERIMENTAL-ANIMALS

Experiments were performed to assess the pharmacology of a novel inhibitor of GABA uptake, Cl‐966 ([1‐[2‐[bis 4‐(trifluoromethyl)phenyl]methoxy]ethyl]‐1,2,5,6‐tetrahydro‐3‐pyridinecarboxylic acid, HCl salt; the molecular weight of the free acid is 473.8). Cl‐966 potently inhibits tritiated GABA uptake into rat hippocampal slices in vitro (lC50 = 304 nM). It has no appreciable effect on the uptake of other neurotransmitters tested (aspartate, dopamine, norepinephrine, serotonin) and has low activity in a broad range of neurotransmitter receptor binding assays. When given orally to mice, Cl‐966 prevents tonic extensor seizures from low‐intensity electroshock and prevents pentylenetetrazole‐induced clonic seizures (ED50 = 0.4–1.0 mg/kg). In addition, the hippocampal afterdischarge threshold in kindled rats is increased markedly (ED50 = 2.6 mg/kg p.o.). Despite anticonvulsant effects, higher doses of Cl‐966 reduce the intravenous dose of pentylenetetrazole needed to produce clonus in mice. In mice, rats, dogs, and monkeys, Cl‐966 interferes with normal behavior, causing ataxia, reduced responsivenes and myoclonus. In the hippocampus of anesthetized rats, Cl‐966 increases inhibition measured electrophysiologically. Overflow of endogenous GABA in the striatum (measured with in vivo microdialysis) was also increased. All of these observed effects with Cl‐966 may be explained by its inhibitory effect on GABA uptake. Copyright © 1990 Wiley‐Liss, Inc.