Steroid modulation of the chloride ionophore in rat brain: structure-activity requirements, regional dependence and mechanism of action
Further in vitro studies of steroids active at the gamma-aminobutyric acidA (GABAA) receptor regulated Cl- channel labeled by (35S)-t-butylbicyclophosphorothionate ((35S)TBPS) reveal additional structural requirements necessary for activity. Evaluation of selected steroids for activity against TBPS-induced convulsions show similar requirements for activity. Interestingly, steroids (e.g., 5 alpha-pregnan-3 alpha, 20 alpha-diol) were identified that have high potency but limited efficacy as modulators of (35S)TBPS binding. These characteristics are reminiscent of the clinically useful benzodiazepines (BZs) such as clonazepam. However, interactions between the prototypical anesthetic-barbiturate, sodium pentobarbital, and steroids active at the Cl- channel suggest that they do not share a common site of action as allosteric modulators of (35S)TBPS and BZ receptor binding. The most potent steroid evaluated, 5 alpha-pregnan-3 alpha-ol-20-one, modulates (35S)TBPS binding at low concentrations (IC50 approximately 17 nM) in a regionally dependent manner. All (35S)TBPS binding sites appear to be functionally coupled to a steroid modulatory site. Because several of the active steroids are metabolites of progesterone, their ability to inhibit the binding of (3H)promegestrone to the cytosolic progestin receptor in rat uterus was evaluated. Those steroids showing potent activity at the GABAA receptor-Cl- ionophore were inactive at the intracellular progestin receptor. Such specificity coupled with their high potency provide additional support for the hypothesis that some of these steroids may be involved in the homeostatic regulation of brain excitability via the GABAA-BZ receptor complex.
- Research Organization:
- Univ. of Southern California, Los Angeles (USA)
- OSTI ID:
- 6805271
- Journal Information:
- J. Pharmacol. Exp. Ther.; (United States), Journal Name: J. Pharmacol. Exp. Ther.; (United States) Vol. 246:2; ISSN JPETA
- Country of Publication:
- United States
- Language:
- English
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59 BASIC BIOLOGICAL SCIENCES
AMINO ACIDS
AMINOBUTYRIC ACID
ANIMALS
AUTONOMIC NERVOUS SYSTEM AGENTS
BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
BIOCHEMICAL REACTION KINETICS
BIOLOGICAL FUNCTIONS
BODY
BRAIN
CARBOXYLIC ACIDS
CENTRAL NERVOUS SYSTEM
CENTRAL NERVOUS SYSTEM AGENTS
CHLORIDES
CHLORINE COMPOUNDS
DAYS LIVING RADIOISOTOPES
DRUGS
EVEN-ODD NUCLEI
FEMALE GENITALS
FUNCTIONS
HALIDES
HALOGEN COMPOUNDS
IN VITRO
ISOTOPE APPLICATIONS
ISOTOPES
KINETICS
LABELLED COMPOUNDS
LIGHT NUCLEI
MAMMALS
MEMBRANE PROTEINS
MICE
NERVOUS SYSTEM
NEUROREGULATORS
NUCLEI
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANS
PREGNANES
PROTEINS
PSYCHOTROPIC DRUGS
RADIOISOTOPES
RATS
REACTION KINETICS
RECEPTORS
RODENTS
STEROIDS
STRUCTURE-ACTIVITY RELATIONSHIPS
SULFUR 35
SULFUR ISOTOPES
TRACER TECHNIQUES
TRANQUILIZERS
TRITIUM COMPOUNDS
UTERUS
VERTEBRATES