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Glycine Antagonists Structurally Related to 4,5,6,7‐Tetrahydroisoxazolo[5,4‐ c ]pyridin‐3‐ol Inhibit Binding of [ 3 H]Strychnine to Rat Brain Membranes
Author(s) -
Braestrup Claus,
Nielsen Mogens,
KrogsgaardLarsen Povl
Publication year - 1986
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1986.tb00667.x
Subject(s) - strychnine , brucine , glycine receptor , chemistry , glycine , antagonist , agonist , sodium , gaba receptor antagonist , stereochemistry , receptor , bicuculline , biochemistry , amino acid , organic chemistry
[ 3 H]Strychnine binding to rat pons + medulla membranes was 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 [ 3 H]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 [ 3 H]strychnine binding, with a K i of 1,400 n M . The K i value for strychnine was 7.0 n M , whereas the K i value for the mixed γ‐aminobutyric acid (GABA)/glycine antagonist 3α‐hydroxy‐16–imino‐5β‐17–aza‐androstan‐11–one (RU 5,135) was only 4.6 n M . Sodium chloride (1,000 m M ) enhanced the affinity of strychnine, brucine, isostrychnine, and the nonselective GABA antagonist pitrazepin for [ 3 H]strychnine binding sites, whereas the affinities of glycine, β‐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 antagonist 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.