Enantiomers of cis-constrained and flexible 2-substituted GABA analogues exert opposite effects at recombinant GABAC receptors

Deborah L. Crittenden, Anna Park, Jian Qiu, Richard B. Silverman, Rujee K. Duke, Graham A.R. Johnston, Meredith J.T. Jordan, Mary Chebib*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

The effects of the enantiomers of a number of flexible and cis-constrained GABA analogues were tested on GABAC receptors expressed in Xenopus laevis oocytes using two-electrode voltage-clamp electrophysiology. (1S,2R)-cis-2-Aminomethylcyclopropane-1-carboxylic acid ((+)-CAMP), a potent and full agonist at the ρ1 (EC50 ≈ 40 μM, Imax ≈ 100%) and ρ 2 (EC50 ≈ 17 μM, Imax ≈ 100%) receptor subtypes, was found to be a potent partial agonist at ρ3 (EC 50 ≈ 28 μM, Imax ≈ 70%). (1R,2S)-cis-2- Aminomethylcyclopropane-1-carboxylic acid ((-)-CAMP), a weak antagonist at human ρ1 (IC50 ≈ 890 μM) and ρ2 (IC50 ≈ 400 μM) receptor subtypes, was also found to be a moderately potent antagonist at rat ρ3 (IC50 ≈ 180 μM). Similarly, (1R,4S)-4- aminocyclopent-2-ene-1-carboxylic acid ((+)-ACPECA) was a full agonist at ρ1 (EC50 ≈ 135 μM, Imax ≈ 100%) and ρ2 (EC 50 ≈ 60 μM, Imax ≈ 100%), but only a partial agonist at ρ3 (EC50 ≈ 112 μM, Imax ≈ 37 %), while (1S,4R)-4-aminocyclopent-2-ene-1-carboxylic acid ((-)-ACPECA) was a weak antagonist at all three receptor subtypes (IC50 ≫ 300 μM). 4-Amino-(S)-2-methylbutanoic acid ((S)-2MeGABA) and 4-amino-(R)-2-methylbutanoic acid ((R)-2MeGABA) followed the same trend, with (S)-2MeGABA acting as a full agonist at the ρ1 (EC50 ≈ 65 μM, Imax ≈ 100%), and ρ2 (EC50 ≈ 20 μM, Imax ≈ 100%) receptor subtypes, and a partial agonist at ρ3 (EC50 ≈ 25 μM, Imax ≈ 90%). (R)-2MeGABA, however, was a moderately potent antagonist at all three receptor subtypes (IC50 ≈ 16 μM at ρ1, 125 μM at ρ2 and 35 μM at ρ3). On the basis of these expanded biological activity data and the solution-phase molecular structures obtained at the MP2/6-31+G* level of ab initio theory, a rationale is proposed for the genesis of this stereoselectivity effect.

Original languageEnglish (US)
Pages (from-to)447-455
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume14
Issue number2
DOIs
StatePublished - Jan 15 2006

Keywords

  • (+)-ACPECA, 1R, 4S)-4-aminocyclopent- 2-ene-1-carboxylic acid
  • (+)-CAMP, (1S,2R)-cis-2- aminomethylcyclopropane-1-carboxylic acid
  • (-)-CAMP,(1R, 2S)-cis-2- aminomethylcyclopropane-1-carboxylic acid
  • GABA, γ-aminobutyric acid

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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