Enhanced 5-HT metabolism and synthesis rate by the new selective r5-HT1B receptor antagonist, NAS-181 in the rat brain

• Published in: Neuropharmacology Vol. 39; no. 4; pp. 553 - 560
• Main Authors: STENFORS, C, HONG YU, ROSS, S. B
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 14.02.2000
• Subjects: 5-Hydroxytryptophan - metabolism; Animals; Benzopyrans - pharmacology; Biological and medical sciences; Brain - metabolism; Dopamine - metabolism; Male; Medical sciences; Morpholines - pharmacology; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1B; Receptors, Serotonin - biosynthesis; Receptors, Serotonin - drug effects; Receptors, Serotonin - metabolism; Serotonin - metabolism; Serotonin Antagonists - pharmacology; Serotoninergic system; Dopamine; Rat; Serotonin; Metabolite; Rodentia; Central nervous system; Biosynthesis; 5-HT1 Serotonine receptor; Metabolism; Biological activity; Dose activity relation; Vertebrata; Mammalia; Animal; Subcutaneous administration; Antagonist; Pharmacokinetics; Brain (vertebrata)
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/S0028-3908(99)00173-2

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.