Glycine Antagonists Structurally Related to 4,5,6,7‐Tetrahydroisoxazolo[5,4‐c]pyridin‐3‐ol Inhibit Binding of [3H]Strychnine to Rat Brain Membranes

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Abstract
[3H]Strychnine binding to rat pons + medulla membranes were used as a measure of glycine receptors or glycine receptor-coupled chloride channels in vitro. A series of compounds structurally related to 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), which previously were shown to antagonize glycine responses in cat spinal cord, inhibited [3H]strychnine binding in micromolar concentrations. The most potent of these glycine antagonists, 5,6,7,8-tetrahydro-4-H-isoxazolo[3,4-d]azepin-3-ol (iso-THAZ), was also the most potent inhibitor of [3H]strychnine binding, witha Ki of 1,400 nM. The Ki value for strychnine was 7.0 nM, whereas the Ki value for the mixed .gamma.-aminobutyric acid (GABA)/glycine antagonist 3.alpha.-hydroxy-16-imino-5.beta.-17-aza-androstan-11-one (RU 5135) was only 4.6 nM. Sodium chloride (1,000 mM) enhanced the affinity of strychnine, brucine, isostrychnine, and the nonselective GABA antagonist pitrazepin for [3H]strychnine binding sites, whereas the affinities of glycine, .beta.-alanine, and taurine were reduced. These sodium chloride shifts, however, were not predictive of antagonist or agonist properties, since the sodium chloride shift for the glycine anagonist iso-THAZ and of the other THIP-related antagonists were similar to those of the glycine-like agonists. The various sodium chloride shifts show that different groups of ligands bind to glycine receptor sites in different ways.