title: Ciproxifan, a histamine H3receptor antagonist, reversibly inhibits monoamine oxidase A and B.
abstract: Ciproxifan is a well-investigated histamine H3receptor (H3R) inverse agonist/antagonist, showing an exclusively high species-specific affinity at rodent compared to human H3R. It is well studied as reference compound for H3R in rodent models for neurological diseases connected with neurotransmitter dysregulation, e.g. attention deficit hyperactivity disorder or Alzheimer's disease. In a screening for potential monoamine oxidase A and B inhibition ciproxifan showed efficacy on both enzyme isoforms. Further characterization of ciproxifan revealed IC50values in a micromolar concentration range for human and rat monoamine oxidases with slight preference for monoamine oxidase B in both species. The inhibition by ciproxifan was reversible for both human isoforms. Regarding inhibitory potency of ciproxifan on rat brain MAO, these findings should be considered, when using high doses in rat models for neurological diseases. As the H3R and monoamine oxidases are all capable of affecting neurotransmitter modulation in brain, we consider dual targeting ligands as interesting approach for treatment of neurological disorders. Since ciproxifan shows only moderate activity at human targets, further investigations in animals are not of primary interest. On the other hand, it may serve as starting point for the development of dual targeting ligands.
authors.affiliation: Heinrich Heine University Duesseldorf, Institute of Pharmaceutical and Medicinal Chemistry, Universitaetsstr. 1, 40225 Duesseldorf, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Hagenow
authors.affiliation: Department of Hormone Biochemistry, Medical University of Lodz, Zeligowskiego 7/9, Pl 90-752 Lodz, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Stasiak
authors.affiliation: Biomedical Sciences Research Complex, University of St Andrews, North Haugh, St Andrews KY16 9ST, United Kingdom.
authors.forename: R R
authors.initials: RR
authors.lastname: Ramsay
authors.affiliation: Heinrich Heine University Duesseldorf, Institute of Pharmaceutical and Medicinal Chemistry, Universitaetsstr. 1, 40225 Duesseldorf, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Stark
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology; D006633:Histamine Antagonists / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017208:Rats, Wistar; D018100:Receptors, Histamine H3 / Q000378:metabolism*
chemical_list: D006633:Histamine Antagonists; D007093:Imidazoles; D008996:Monoamine Oxidase Inhibitors; D018100:Receptors, Histamine H3; C115705:ciproxifan; D008995:Monoamine Oxidase