Characterization of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) binding sites in C57BL/6 mouse brain: Mutual effects of monoamine oxidase inhibitors and σ ligands on MPTP and σ binding sites

Yossef Itzhak, Deborah C Mash, She Hui Zhang, Ira Stein

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Abstract

N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces Parkinson-like symptoms in humans, nonhuman primates, and mice. Several studies suggest that MPTP is metabolized by monoamine oxidase (MAO) type B to yield N-methyl-4-phenylpyridinium (MPP+), which is responsible for the neurotoxic effects of the drug. In the present study, the pharmacological properties of [3H]MPTP binding sites in C57BL/6 mouse brain membranes were investigated, and a possible relationship to the σ binding sites was examined. Both equilibrium binding experiments and kinetic assays indicate that [3H]MPTP labels two distinct binding sites in C57BL/6 mouse brain. The high affinity [3H]MPTP binding sites (Kd = 13 NM) are selectively blocked by the MAO type A inhibitor clorgyline, and the residual low affinity [3H]MPTP sites (Kd = 1100 NM) display the pharmacological specificity of MAO-B binding sites. In contrast, the low affinity [3H]MPTP binding sites are blocked by the selective MAO-B inhibitor (-)-deprenyl, and the drug-specificity profile of the remaining high affinity sites is consistent with the properties of MAO-A binding sites. The affinities of several MAO inhibitors tested and of MPTP for the high affinity MPTP/MAO-A binding sites correlate well (r = 0.96) with their affinities for the σ binding sites labeled with (+)-[3H]-3-(3-hydroxyphenyl)-N-1-(propyl)piperidine [(+)-[3H]-3-PPP]. The σ receptor ligand (+)-3-PPP displays moderately high affinity for the MPTP/MAO-A binding sites but negligible affinity for MPTP/ MAO-B sites. Moreover, (+)-3-PPP alters the dissociation kinetics of MPTP from the high affinity MPTP/MAO-A sites. The finding that [3H]MPTP labels MAO-B sites supports the hypothesis that the drug is a substrate for these enzyme binding sites. However, the finding that the high affinity sites, labeled by [3H] MPTP, are particularly sensitive to MAO-A inhibitors, which also display high affinity for the σ binding sites, may suggest a possible relationship between MAO-A and σ binding sites. In turn, the kinetic experiments imply that σ ligands [i.e., (+)-3-PPP] may allosterically modulate the binding to MAO-A binding sites.

Original languageEnglish
Pages (from-to)385-393
Number of pages9
JournalMolecular Pharmacology
Volume39
Issue number3
StatePublished - Mar 1 1991

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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Monoamine Oxidase Inhibitors
Inbred C57BL Mouse
Monoamine Oxidase
Binding Sites
Ligands
Brain
Clorgyline
Pharmaceutical Preparations
Pharmacology
1-Methyl-4-phenylpyridinium
Selegiline

ASJC Scopus subject areas

  • Pharmacology

Cite this

Characterization of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) binding sites in C57BL/6 mouse brain : Mutual effects of monoamine oxidase inhibitors and σ ligands on MPTP and σ binding sites. / Itzhak, Yossef; Mash, Deborah C; Zhang, She Hui; Stein, Ira.

In: Molecular Pharmacology, Vol. 39, No. 3, 01.03.1991, p. 385-393.

Research output: Contribution to journalArticle

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title = "Characterization of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) binding sites in C57BL/6 mouse brain: Mutual effects of monoamine oxidase inhibitors and σ ligands on MPTP and σ binding sites",
abstract = "N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces Parkinson-like symptoms in humans, nonhuman primates, and mice. Several studies suggest that MPTP is metabolized by monoamine oxidase (MAO) type B to yield N-methyl-4-phenylpyridinium (MPP+), which is responsible for the neurotoxic effects of the drug. In the present study, the pharmacological properties of [3H]MPTP binding sites in C57BL/6 mouse brain membranes were investigated, and a possible relationship to the σ binding sites was examined. Both equilibrium binding experiments and kinetic assays indicate that [3H]MPTP labels two distinct binding sites in C57BL/6 mouse brain. The high affinity [3H]MPTP binding sites (Kd = 13 NM) are selectively blocked by the MAO type A inhibitor clorgyline, and the residual low affinity [3H]MPTP sites (Kd = 1100 NM) display the pharmacological specificity of MAO-B binding sites. In contrast, the low affinity [3H]MPTP binding sites are blocked by the selective MAO-B inhibitor (-)-deprenyl, and the drug-specificity profile of the remaining high affinity sites is consistent with the properties of MAO-A binding sites. The affinities of several MAO inhibitors tested and of MPTP for the high affinity MPTP/MAO-A binding sites correlate well (r = 0.96) with their affinities for the σ binding sites labeled with (+)-[3H]-3-(3-hydroxyphenyl)-N-1-(propyl)piperidine [(+)-[3H]-3-PPP]. The σ receptor ligand (+)-3-PPP displays moderately high affinity for the MPTP/MAO-A binding sites but negligible affinity for MPTP/ MAO-B sites. Moreover, (+)-3-PPP alters the dissociation kinetics of MPTP from the high affinity MPTP/MAO-A sites. The finding that [3H]MPTP labels MAO-B sites supports the hypothesis that the drug is a substrate for these enzyme binding sites. However, the finding that the high affinity sites, labeled by [3H] MPTP, are particularly sensitive to MAO-A inhibitors, which also display high affinity for the σ binding sites, may suggest a possible relationship between MAO-A and σ binding sites. In turn, the kinetic experiments imply that σ ligands [i.e., (+)-3-PPP] may allosterically modulate the binding to MAO-A binding sites.",
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N2 - N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces Parkinson-like symptoms in humans, nonhuman primates, and mice. Several studies suggest that MPTP is metabolized by monoamine oxidase (MAO) type B to yield N-methyl-4-phenylpyridinium (MPP+), which is responsible for the neurotoxic effects of the drug. In the present study, the pharmacological properties of [3H]MPTP binding sites in C57BL/6 mouse brain membranes were investigated, and a possible relationship to the σ binding sites was examined. Both equilibrium binding experiments and kinetic assays indicate that [3H]MPTP labels two distinct binding sites in C57BL/6 mouse brain. The high affinity [3H]MPTP binding sites (Kd = 13 NM) are selectively blocked by the MAO type A inhibitor clorgyline, and the residual low affinity [3H]MPTP sites (Kd = 1100 NM) display the pharmacological specificity of MAO-B binding sites. In contrast, the low affinity [3H]MPTP binding sites are blocked by the selective MAO-B inhibitor (-)-deprenyl, and the drug-specificity profile of the remaining high affinity sites is consistent with the properties of MAO-A binding sites. The affinities of several MAO inhibitors tested and of MPTP for the high affinity MPTP/MAO-A binding sites correlate well (r = 0.96) with their affinities for the σ binding sites labeled with (+)-[3H]-3-(3-hydroxyphenyl)-N-1-(propyl)piperidine [(+)-[3H]-3-PPP]. The σ receptor ligand (+)-3-PPP displays moderately high affinity for the MPTP/MAO-A binding sites but negligible affinity for MPTP/ MAO-B sites. Moreover, (+)-3-PPP alters the dissociation kinetics of MPTP from the high affinity MPTP/MAO-A sites. The finding that [3H]MPTP labels MAO-B sites supports the hypothesis that the drug is a substrate for these enzyme binding sites. However, the finding that the high affinity sites, labeled by [3H] MPTP, are particularly sensitive to MAO-A inhibitors, which also display high affinity for the σ binding sites, may suggest a possible relationship between MAO-A and σ binding sites. In turn, the kinetic experiments imply that σ ligands [i.e., (+)-3-PPP] may allosterically modulate the binding to MAO-A binding sites.

AB - N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces Parkinson-like symptoms in humans, nonhuman primates, and mice. Several studies suggest that MPTP is metabolized by monoamine oxidase (MAO) type B to yield N-methyl-4-phenylpyridinium (MPP+), which is responsible for the neurotoxic effects of the drug. In the present study, the pharmacological properties of [3H]MPTP binding sites in C57BL/6 mouse brain membranes were investigated, and a possible relationship to the σ binding sites was examined. Both equilibrium binding experiments and kinetic assays indicate that [3H]MPTP labels two distinct binding sites in C57BL/6 mouse brain. The high affinity [3H]MPTP binding sites (Kd = 13 NM) are selectively blocked by the MAO type A inhibitor clorgyline, and the residual low affinity [3H]MPTP sites (Kd = 1100 NM) display the pharmacological specificity of MAO-B binding sites. In contrast, the low affinity [3H]MPTP binding sites are blocked by the selective MAO-B inhibitor (-)-deprenyl, and the drug-specificity profile of the remaining high affinity sites is consistent with the properties of MAO-A binding sites. The affinities of several MAO inhibitors tested and of MPTP for the high affinity MPTP/MAO-A binding sites correlate well (r = 0.96) with their affinities for the σ binding sites labeled with (+)-[3H]-3-(3-hydroxyphenyl)-N-1-(propyl)piperidine [(+)-[3H]-3-PPP]. The σ receptor ligand (+)-3-PPP displays moderately high affinity for the MPTP/MAO-A binding sites but negligible affinity for MPTP/ MAO-B sites. Moreover, (+)-3-PPP alters the dissociation kinetics of MPTP from the high affinity MPTP/MAO-A sites. The finding that [3H]MPTP labels MAO-B sites supports the hypothesis that the drug is a substrate for these enzyme binding sites. However, the finding that the high affinity sites, labeled by [3H] MPTP, are particularly sensitive to MAO-A inhibitors, which also display high affinity for the σ binding sites, may suggest a possible relationship between MAO-A and σ binding sites. In turn, the kinetic experiments imply that σ ligands [i.e., (+)-3-PPP] may allosterically modulate the binding to MAO-A binding sites.

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