Binding interactions of convulsant and anticonvulsant gamma-butyrolactones and gamma-thiobutyrolactones with the picrotoxin receptor

Journal Article · Wed Aug 01 00:00:00 EDT 1990 · Journal of Pharmacology and Experimental Therapeutics; (USA)

OSTI ID:6795786

Holland, K D; McKeon, A C; Covey, D F; Ferrendelli, J A ^[1]

---

1. Washington Univ. School of Medicine, St. Louis, MO (USA)

Alkyl-substituted gamma-butyrolactones (GBLs) and gamma-thiobutyrolactones (TBLs) are neuroactive chemicals. beta-Substituted compounds are convulsant, whereas alpha-alkyl substituted GBLs and TBLs are anticonvulsant. The structural similarities between beta-alkyl GBLs and the convulsant picrotoxinin suggested that alkyl substituted GBLs and TBLs act at the picrotoxin receptor. To test this hypothesis we examined the interactions of convulsant and anticonvulsant GBLs and TBLs with the picrotoxin, benzodiazepine and gamma-aminobutyric acid (GABA) binding sites of the GABA receptor complex. All of these convulsants and anticonvulsants studied competitively displaced 35S-t-butylbicyclophosphorothionate (35S-TBPS), a ligand that binds to the picrotoxin receptor. This inhibition of 35S-TBPS binding was not blocked by the GABA antagonist bicuculline methobromide. The convulsant GBLs and TBLs also partially inhibited (3H)muscimol binding to the GABA site and (3H)flunitrazepam binding to the benzodiazepine site, but they did so at concentrations substantially greater than those that inhibited 35S-TBPS binding. The anticonvulsant GBLs and TBLs had no effect on either (3H)muscimol or (3H)flunitrazepam binding. In contrast to the GBLs and TBLs, pentobarbital inhibited TBPS binding in a manner that was blocked by bicuculline methobromide, and it enhanced both (3H)flunitrazepam and (3H)muscimol binding. Both ethosuximide and tetramethylsuccinimide, neuroactive compounds structurally similar to GBLs, competitively displaced 35S-TBPS from the picrotoxin receptor and both compounds were weak inhibitors of (3H) muscimol binding. In addition, ethosuximide also partially diminished (3H)flunitrazepam binding. These data demonstrate that the site of action of alkyl-substituted GBLs and TBLs is different from that of GABA, barbiturates and benzodiazepines.

• OSTI ID: 6795786
• Journal Information: Journal of Pharmacology and Experimental Therapeutics; (USA), Journal Name: Journal of Pharmacology and Experimental Therapeutics; (USA) Vol. 254:2; ISSN 0022-3565; ISSN JPETA
• Country of Publication: United States
• Language: English

Related Subjects

550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
AMINO ACIDS
AMINOBUTYRIC ACID
ANIMALS
ANTICONVULSANTS
AUTONOMIC NERVOUS SYSTEM AGENTS
BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
BIOCHEMICAL REACTION KINETICS
CARBOXYLIC ACIDS
CENTRAL NERVOUS SYSTEM AGENTS
CENTRAL NERVOUS SYSTEM DEPRESSANTS
CPB
DAYS LIVING RADIOISOTOPES
DRUGS
EVEN-ODD NUCLEI
HYDROGEN COMPOUNDS
ISOTOPE APPLICATIONS
ISOTOPES
KINETICS
LIGANDS
LIGHT NUCLEI
MAMMALS
MEMBRANE PROTEINS
NEUROREGULATORS
NUCLEI
ORGANIC ACIDS
ORGANIC COMPOUNDS
PROTEINS
PSYCHOTROPIC DRUGS
RADIOISOTOPES
RATS
REACTION KINETICS
RECEPTORS
RODENTS
STRUCTURE-ACTIVITY RELATIONSHIPS
SULFUR 35
SULFUR ISOTOPES
TRACER TECHNIQUES
TRANQUILIZERS
TRITIUM COMPOUNDS
VERTEBRATES