title: Effect of sabcomeline on muscarinic and dopamine receptor binding in intact mouse brain.
abstract: Sabcomeline [(R-(Z)-(+)-alpha-(methoxyiamino)-1-azabicyclo[2.2.2]octane-3-acetonitrile)] is a potent and functionally selective muscarinic M1 receptor partial agonist. However, little is known of the binding properties of sabcomeline under in vivo conditions. In this study, muscarinic receptor occupancy by sabcomeline in mouse brain regions and heart was estimated using [3H]quinuclidinyl benzilate (QNB) and [3H]N-methylpiperidyl benzilate (NMPB) as radioligands. In the cerebral cortex, hippocampus, and striatum, the estimated IC50 value of sabcomeline for [3H]NMPB binding was almost 0.2 mg/kg. Sabcomeline was not a selective ligand to M1 receptors as compared with biperiden in vivo. In the cerebral cortex, maximum receptor occupancy was observed about 1 hr after intravenous injection of sabcomeline (0.3 mg/kg), and the binding availability of mACh receptors had almost returned to the control level by 3-4 hr. These findings indicated that the binding kinetics of sabcomeline is rather rapid in mouse brain. Examination of dopamine D2 receptor binding revealed that sabcomeline affected the kinetics of both [3H]raclopride and [3H]N-methylspiperone (NMSP) binding in the striatum. It significantly decreased the k3 and k4 of [3H]raclopride binding resulting in an increase in binding potential (BP = k3/k4 = Bmax/Kd) in sabcomeline-treated mice, and an approximately 15% decrease in k3 of [3H]NMSP binding was also observed. Although the mechanism is still unclear, sabcomeline altered dopamine D2 receptor affinity or availability by modulations via neural networks.
authors.affiliation: Department of Medical Physics, School of Allied Health Sciences, Faculty of Medicine, Osaka University, Suita, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Hosoi
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Junichi
authors.initials: J
authors.lastname: Ishida
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Osamu
authors.initials: O
authors.lastname: Inoue
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism*; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000378:metabolism; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000378:metabolism; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism; D003947:Diagnostic Techniques, Radioisotope; D004305:Dose-Response Relationship, Drug; D007097:Imines; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008815:Mice, Inbred Strains; D009928:Organ Specificity; D010880:Piperidines / Q000493:pharmacokinetics*; D011485:Protein Binding; D011812:Quinuclidines; D011813:Quinuclidinyl Benzilate / Q000493:pharmacokinetics*; D020891:Raclopride / Q000493:pharmacokinetics; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism*; D013134:Spiperone / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D007097:Imines; D010880:Piperidines; D011812:Quinuclidines; D019275:Radiopharmaceuticals; D011954:Receptors, Dopamine; C433775:methylpiperidylbenzilate; D014316:Tritium; D020891:Raclopride; D013134:Spiperone; D011813:Quinuclidinyl Benzilate; C109640:sabcomeline