Binding of sigma-ligands to C57BL/6 mouse brain membranes: effects of monoamine oxidase inhibitors and subcellular distribution studies suggest the existence of sigma-receptor subtypes.
Our preliminary studies indicated that certain monoamine oxidase (MAO) inhibitors display high affinity for the sigma-binding sites labeled with (+)[3H]-3-(3-hydroxyphenyl)-N-1-(propyl)piperidine [(+)[3H]-3-PPP] in C57BL/6 mouse brain (Itzhak, Y., and Kassim, C. D.: Eur. J. Pharmacol. 176: 107-108, 1990). In the present study, the drug specificity and the subcellular distribution of (+)[3H]-3-PPP, (+)[3H]-N-allylnormetazocine [(+)[3H]SKF 10047] and [3H]1,3-di-o-tolyl-guanidine ([3H]DTG) binding sites in C57BL/6 mouse brain were investigated, and the properties of clorgyline interaction with the (+)-3-PPP/sigma-binding site(s) were examined. (+)[3H]-3-PPP binding, but not [3H]DTG binding, is inhibited by low concentrations (nM) of the dextrorotatory (+)-isomers of SKF 10047, 3-PPP and deprenyl and the type A MAO inhibitor, clorgyline. The haloperidol-sensitive/(+)[3H]SKF 10047 binding sites display virtually identical sensitivity towards the MAO inhibitors as (+)-3-PPP binding sites. These observations suggest a distinction between [3H]DTG and (+)[3H]-3-PPP/(+)[3H]SKF 10047 binding sites in the mouse brain. Clorgyline interaction with (+)-3-PPP/sigma-sites is competitive and reversible unlike the interaction of clorgyline with MAO-A. The sigma-ligands tested do not inhibit MAO activity and bind to sites that are apparently distinct from the MAO binding sites labeled with [3H]-N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. However, the mitochondrial fraction of the mouse brain that expresses MAO activity and high density of [3H]-N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine binding sites also comprises high density of (+)-3-PPP/(+)SKF 10047 binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)
Itzhak
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Y
Department of Biochemistry and Molecular Biology, REPSCEND Laboratories, University of Miami School of Medicine, Florida 33101.
Stein
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I
Zhang
S H
SH
Kassim
C O
CO
Cristante
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D
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism*; D006146:Guanidines / Q000378:metabolism; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008996:Monoamine Oxidase Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D010620:Phenazocine / Q000031:analogs & derivatives / Q000378:metabolism; D010880:Piperidines / Q000378:metabolism; D011957:Receptors, Opioid / Q000032:analysis* / Q000378:metabolism; D017480:Receptors, sigma
D006146:Guanidines; D008024:Ligands; D008996:Monoamine Oxidase Inhibitors; D010880:Piperidines; D011957:Receptors, Opioid; D017480:Receptors, sigma; C012134:SK&F 10047; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C026539:preclamol; D010620:Phenazocine; C050232:1,3-ditolylguanidine