Effects of histamine H3-receptor ligands on brain monoamine oxidase in various mammalian species.
The effects of an H3 agonist, R-alpha-methylhistamine (alpha-MeHA), and an H3 antagonist, thioperamide, on monoamine oxidase (MAO) activity in the hypothalamus of rat, monkey and human brains were compared in vitro. The histamine H(3)-receptor ligands competitively inhibited MAO-B, but noncompetitively inhibited MAO-A in all three mammalian species. However, alpha-MeHA inhibited MAO-A more potently than MAO-B at high concentrations in all three species. The K(i) values for MAO-A of alpha-MeHA in hypothalamic homogenates of rat, monkey and human brains were estimated to be 1.1, 1.2 and 1.9 mM, respectively, suggesting that alpha-MeHA cannot behave as a substrate for the MAO inhibitor. In contrast, rat, monkey and human brain MAO-B activities were inhibited by thioperamide, with respective K(i) values of 174.6, 8.2 and 10.8 microM, more potently than MAO-A activity. These results indicate that thioperamide, which elicits a strong activation of histamine release and turnover to N-tele-methylhistamine from histamine, competitively inhibits the conversion of N-tele-methylhistamine to N-tele-methylimidazoleacetic acid in human and monkey brains where MAO-B predominates.
Sakurai
E
E
Department of Pharmaceutics I, Tohoku Pharmaceutical University, 4-1 Komatsushima 4-chome, Aoba-ku, Sendai 981-8558, Japan. sakuraie@tohoku-pharm.ac.jp
Sakurai
E
E
Tanaka
Y
Y
Watanabe
T
T
Singh Jossan
S
S
Oreland
L
L
D000368:Aged; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006632:Histamine / Q000378:metabolism; D017442:Histamine Agonists / Q000494:pharmacology*; D006633:Histamine Antagonists / Q000494:pharmacology*; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects* / Q000201:enzymology; D007093:Imidazoles / Q000378:metabolism; D008024:Ligands; D008251:Macaca; D008761:Methylhistamines / Q000378:metabolism / Q000494:pharmacology; D008875:Middle Aged; D008995:Monoamine Oxidase / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000187:drug effects* / Q000378:metabolism; D013347:Subcellular Fractions / Q000187:drug effects* / Q000201:enzymology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D017442:Histamine Agonists; D006633:Histamine Antagonists; D007093:Imidazoles; D008024:Ligands; D008761:Methylhistamines; D010880:Piperidines; D018100:Receptors, Histamine H3; C002667:methylimidazoleacetic acid; C069357:alpha-methylhistamine; D006632:Histamine; D008995:Monoamine Oxidase; C052075:thioperamide; C020404:tele-methylhistamine