title: An evaluation of the effect of NAS-181, a new selective 5-HT(1B) receptor antagonist, on extracellular 5-HT levels in rat frontal cortex.
abstract: In the mammalian brain 5-HT(1B) receptors are present as autoreceptors regulating the release of serotonin (5-HT) by inhibitory feedback. The antagonistic properties of NAS-181 ((R)-(+)-2-[[[3-(Morpholinomethyl)-2H-chromen-8-yl]oxy]methyl] morpholine methane sulfonate), a new selective antagonist for the rodent 5-HT(1B) receptor, were determined by using an agonist-induced decrease of extracellular 5-HT. The 5-HT(1B) receptor agonist CP93129 (0.030.3 microM) applied by reversed microdialysis, dose-dependently reduced 5-HT levels in rat frontal cortex. The suppressant effect of CP93129 (0.1 microM) was smaller in the presence of fluvoxamine (3-10 microM), a 5-HT reuptake inhibitor. The effects of NAS-181 on CP93129 were compared with GR127935, a mixed 5-HT (1B/1D) receptor antagonist, and SB224289, a 5-HT(1B) receptor antagonist. Both in the presence and absence of fluvoxamine, the suppressant effect of CP93129 on extracellular 5-HT was attenuated by NAS-181 (1 microM) and GR127935 (10 microM), but not by SB224289 (1 microM). In the absence of fluvoxamine, GR127935, SB224289 and NAS-181 all reduced 5-HT levels, suggesting partial agonistic properties of these compounds. In conclusion, the results show that NAS-181 is a potent 5-HT(1B) receptor antagonist.
authors.affiliation: Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
authors.forename: Lotte
authors.initials: L
authors.lastname: de Groote
authors.forename: André A
authors.initials: AA
authors.lastname: Klompmakers
authors.forename: Berend
authors.initials: B
authors.lastname: Olivier
authors.forename: Herman G M
authors.initials: HG
authors.lastname: Westenberg
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D045604:Extracellular Fluid / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D016666:Fluvoxamine / Q000494:pharmacology; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*; D010069:Oxadiazoles / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010881:Piperidones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044302:Receptor, Serotonin, 5-HT1B / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013141:Spiro Compounds / Q000494:pharmacology; D013997:Time Factors
chemical_list: D001578:Benzopyrans; D016666:Fluvoxamine; D009025:Morpholines; D010069:Oxadiazoles; D010879:Piperazines; D010881:Piperidones; D044302:Receptor, Serotonin, 5-HT1B; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D013141:Spiro Compounds; C112429:2-(((3-(morpholinylmethyl)-2H-chromen-8-yl)oxy)methyl)morpholine; C108518:SB 22489G; C090701:GR 127935