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.
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