Pharmacology of CI-966

A potent GABA uptake inhibitor, in vitro and in experimental animals

C. P. Taylor, M. G. Vartanian, R. D. Schwarz, D. M. Rock, M. J. Callahan, M. D. Davis

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Experiments were performed to assess the pharmacology of a novel inhibitor of GABA uptake, CI-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). CI-966 potently inhibits tritiated GABA uptake into rat hippocampal slices in vitro (IC50 = 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, CI-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 CI-966 reduce the intravenous dose of pentylenetetrazole needed to produce clonus in mice. In mice, rats, dogs, and monkeys, CI-966 interferes with normal behavior, causing ataxia, reduced responsiveness and myoclonus. In the hippocampus of anesthetized rats, CI-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 CI-966 may be explained by its inhibitor effect on GABA uptake.

Original languageEnglish (US)
Pages (from-to)195-215
Number of pages21
JournalDrug Development Research
Volume21
Issue number3
DOIs
StatePublished - 1990
Externally publishedYes

Fingerprint

GABA Uptake Inhibitors
Animals
Pharmacology
Rats
gamma-Aminobutyric Acid
Pentylenetetrazole
Seizures
Electroshock
Myoclonus
Neurotransmitter Receptor
Niacin
Microdialysis
Ataxia
CI 966
In Vitro Techniques
Aspartic Acid
Anticonvulsants
Inhibitory Concentration 50
Haplorhini
Neurotransmitter Agents

Keywords

  • Anticonvulsant
  • Mice
  • Monkeys
  • Myoclonus
  • Rats

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

Taylor, C. P., Vartanian, M. G., Schwarz, R. D., Rock, D. M., Callahan, M. J., & Davis, M. D. (1990). Pharmacology of CI-966: A potent GABA uptake inhibitor, in vitro and in experimental animals. Drug Development Research, 21(3), 195-215. https://doi.org/10.1002/ddr.430210306

Pharmacology of CI-966 : A potent GABA uptake inhibitor, in vitro and in experimental animals. / Taylor, C. P.; Vartanian, M. G.; Schwarz, R. D.; Rock, D. M.; Callahan, M. J.; Davis, M. D.

In: Drug Development Research, Vol. 21, No. 3, 1990, p. 195-215.

Research output: Contribution to journalArticle

Taylor, CP, Vartanian, MG, Schwarz, RD, Rock, DM, Callahan, MJ & Davis, MD 1990, 'Pharmacology of CI-966: A potent GABA uptake inhibitor, in vitro and in experimental animals', Drug Development Research, vol. 21, no. 3, pp. 195-215. https://doi.org/10.1002/ddr.430210306
Taylor, C. P. ; Vartanian, M. G. ; Schwarz, R. D. ; Rock, D. M. ; Callahan, M. J. ; Davis, M. D. / Pharmacology of CI-966 : A potent GABA uptake inhibitor, in vitro and in experimental animals. In: Drug Development Research. 1990 ; Vol. 21, No. 3. pp. 195-215.
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