SKF 525-A and cytochrome P-450 ligands inhibit with high affinity the binding of ( sup 3 H)dextromethorphan and. sigma. ligands to guinea pig brain
- New York Univ. Medical Center, New York, NY (USA)
The DM{sub 1}/{sigma}{sub 1} site binds dextromethorphan (DM) and {sigma} receptor ligands. The broad binding specificity of this site and its peculiar subcellular distribution prompted us to explore the possibility that this site is a member of the cytochrome P-450 superfamily of enzymes. We tested the effects of the liver microsomal monooxygenase inhibitor SKF 525-A (Proadifen), and other P-450 substrates on the binding of ({sup 3}H)dextromethorphan, ({sup 3}H)3- (3-Hydroxyphenyl) -N- (1-propyl) piperidine and (+)-({sup 3}H)1,3-Di-o-tolyl-guanidine (({sup 3}H)DTG) to the guinea pig brain. SKF 525-A, l-lobeline and GBR-12909 inhibited the binding of the three labeled ligands with nM affinity. Each drug has identical nM K{sub i} values for the high-affinity site labeled by the three ligands. This indicated that they displaced the labeled ligands from the common DM{sub 1}{sigma}{sub 1} site. Debrisoquine and sparteine, prototypical substrates for liver debrisoquine 4-hydroxylase, displayed K{sub i} values of 9-13 and 3-4 {mu}M respectively against the three labeled ligands. These results, the broad specificity of the DM{sub 1}/{sigma}{sub 1} binding site, and its peculiar subcellular distribution, raises the possibility that this binding site is a member of the cytochrome P-450 superfamily of isozymes, rather than a neurotransmitter receptor.
- OSTI ID:
- 5739041
- Journal Information:
- Life Sciences; (USA), Vol. 48:6; ISSN 0024-3205
- Country of Publication:
- United States
- Language:
- English
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DRUGS
BIOCHEMICAL REACTION KINETICS
ENZYME INHIBITORS
AFFINITY
BRAIN
GUANIDINES
GUINEA PIGS
LIGANDS
LIVER
MICROSOMES
MIXED-FUNCTION OXIDASES
PIPERIDINES
RECEPTORS
SUBCELLULAR DISTRIBUTION
TRACER TECHNIQUES
TRITIUM COMPOUNDS
AMINES
ANIMALS
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BODY
CARBONIC ACID DERIVATIVES
CELL CONSTITUENTS
CENTRAL NERVOUS SYSTEM
DIGESTIVE SYSTEM
DISTRIBUTION
ENZYMES
GLANDS
HETEROCYCLIC COMPOUNDS
HYDROGEN COMPOUNDS
ISOTOPE APPLICATIONS
KINETICS
MAMMALS
MEMBRANE PROTEINS
NERVOUS SYSTEM
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
OXIDOREDUCTASES
OXYGENASES
PROTEINS
PYRIDINES
REACTION KINETICS
RIBOSOMES
RODENTS
VERTEBRATES
550201* - Biochemistry- Tracer Techniques