1.
Strychnine-sensitive
glycine receptors are primarily localized in the brainstem and spinal cord where they are the major mediators of postsynaptic inhibition. A compound which acts functionally like a
glycine receptor agonist would be potentially useful as a pharmacological tool and as a therapeutic agent for treating disorders of glycinergic transmission. 2.
MDL 27,531 (4-methyl-3-methylsulphonyl-5-phenyl-4H-1,2,4-triazole) blocked
strychnine-induced tonic extensor
seizures in mice following either intraperitoneal (ED50 = 12.8 mg kg-1; 30 min) or oral (ED50 = 7.3 mg kg-1; 30 min) administration. Time course studies revealed a maximal effect at 30-60 min, though significant activity was still seen after 24 h. 3.
MDL 27,531 was selective in antagonizing
strychnine seizures and little or no activity was seen against
seizures produced by other chemical
convulsants (
bicuculline;
quinolinic acid; mercaptopropionic
acid); by electrical stimuli (maximal electroshock); or by sensory stimuli (audiogenic seizure susceptible mice).
MDL 27,531 blocked
pentylenetetrazol-induced
seizures with an ED50 = 55 mg kg-1. This profile differed from those of the
anticonvulsants diazepam,
valproic acid, and
diphenylhydantoin. 4. The antagonism of
strychnine seizures by
MDL 27,531 occurred at doses that did not produce signs of sedation (suppression of spontaneous motor activity),
motor ataxia (disruption of rotarod performance), muscle relaxation (inhibition of
morphine-induced Straub tail), or CNS depression (potentiation of
hexobarbitone sleep time).
MDL 27,531 had less side effect potential (as derived from ratios obtained from the above measures) relative to those of the known muscle relaxants
diazepam and
baclofen. 5. Although
MDL 27,531 behaved functionally like a selective agonist at the
strychnine-sensitive glycine receptor, the compound did not alter the in vitro binding of [3H]-
strychnine to mice brainstem/spinal cord membranes at concentrations of up to 100 microM. In further in vitro binding assays,
MDL 27,531 at concentrations of up to 100 microM, did not displace the binding of [3H]-
muscimol, [3H]-
flunitrazepam, or["S]-t-butylbicyclophosphorthionate to rat cortical membranes. These
ligands bind to the 7y-aminobutyric
acid (
GABA),
benzodiazepine, and
picrotoxin-
convulsant binding sites, respectively.6.
MDL 27,531 (10-100mgkg-', i.p.) enhanced binding of the
benzodiazepine antagonist [3H]-Ro15-1788 to mouse cerebral cortex in vivo without directly affecting
GABA levels.7.
Ro 15-1788 (16, 32 mg kg-') significantly blocked the
MDL 27,531 antagonism of strychnineinduced
seizures, though this antagonism was not competitive. The same doses of
Ro 15-1788 produced parallel rightward shifts in the dose-response curves for
diazepam inhibition of
pentylenetetrazol-induced
seizures, consistent with a competitive antagonism.8. Thus,
MDL 27,531 acts functionally like an agonist at the
strychnine-sensitive glycine receptor in its capacity to reverse selectively
strychnine-induced
seizures. Though the precise mechanism of action of
MDL 27,531 is unknown,
MDL 27,531 may act at an allosteric site on the
strychnine-sensitive receptor which produces agonist-like activity.