title: Enhanced 5-HT metabolism and synthesis rate by the new selective r5-HT1B receptor antagonist, NAS-181 in the rat brain.
abstract: NAS-181 ((R)-(+)-2-(3-morpholinomethyl-2H-chromen-8-yl) oxymethyl-morpholine methanesulfonate) is a novel rat 5-hydroxytryptamine1B, (r5-HT1B) receptor antagonist with high selectivity. The in vivo effects of NAS-181 on 5-HT metabolism and synthesis in the rat brain were examined. 5-HT metabolism, measured as the ratio 5-hydroxyindoleacetic acid (5-HIAA)/5-HT, was dose-dependently increased in all four brain regions analysed (hypothalamus, hippocampus, frontal cortex and striatum) at doses 0.1 to 20 mg/kg s.c. NAS-181. The enhancement of 5-HT metabolism at the dose 20 mg/kg s.c. was maximal one hour after the injection and was still significant eight hours but not 24 hours after the injection. 5-HT synthesis rate measured as the accumulation of 5-hydroxytryptophan (5-HTP) after inhibition of the aromatic amino acid decarboxylase activity was also elevated by NAS-181 at doses 0.3 to 20 mg/kg s.c. NAS-181 competitively antagonised the decrease in 5-HT metabolism evoked by the r5-HT1B receptor agonist, anpirtoline, in hypothalamus, hippocampus and frontal cortex. Anpirtoline had no effect on 5-HT metabolism in striatum. However, anpirtoline antagonised the enhancement of 5-HT metabolism induced by NAS-181 in striatum. Combined treatment of rats with NAS-181 and the 5-HT1A receptor antagonist, WAY-100635, increased 5'-HT metabolism considerably more than when the compounds were given alone.
authors.affiliation: Preclinical R&D, Astra Arcus AB, Södertälje, Sweden. carina.stenfors@arcus.se.astra.com
authors.forename: C
authors.initials: C
authors.lastname: Stenfors
authors.forename: H
authors.initials: H
authors.lastname: Yu
authors.forename: S B
authors.initials: SB
authors.lastname: Ross
mesh_terms: D006916:5-Hydroxytryptophan / Q000378:metabolism; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000096:biosynthesis / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*
chemical_list: C112429:2-(((3-(morpholinylmethyl)-2H-chromen-8-yl)oxy)methyl)morpholine; D001578:Benzopyrans; D009025:Morpholines; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D012701:Serotonin; D006916:5-Hydroxytryptophan; D004298:Dopamine