Proadifen-sensitive high affinity binding of 3H-alaproclate to liver membranes.
3H-Alaproclate, a selective 5-hydroxytryptamine uptake inhibitor, was found to bind to microsomal membranes from the rat liver with high affinity (KD = 3 nM) and large capacity (Bmax about 2 nmol/g liver). This binding was stereoselective since S-(-)-alaproclate was 30 times more potent than the R-(+)-enantiomer to displace the 3H-labelled racemate. Proadifen (SKF 525A), an inhibitor of cytochrome P-450, displaced the 3H-alaproclate binding with the same, high affinity (Ki = 3 nM) as alaproclate itself. Repeated treatment with phenobarbital sodium (5 x 75 mg/kg intraperitoneally) increased the number of alaproclate binding sites 7-8 times without changing the affinity. However, most of the phenobarbital induced 3H-alaproclate binding was not displaceable by proadifen, showing the presence of at least two different high affinity binding sites. The possible involvement of cytochrome P-450 in the alaproclate binding is discussed.
Department of Biochemical Neuropharmacology, Astra Alab AB, Södertlje, Sweden.
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D000409:Alanine / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D000928:Antidepressive Agents / Q000378:metabolism*; D001667:Binding, Competitive; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism
D000928:Antidepressive Agents; D011335:Proadifen; C025293:alaproclate; D000409:Alanine; D010634:Phenobarbital