(R)-(+)-2-[[[3-(Morpholinomethyl)-2H-chromen-8-yl]oxy]methyl]morpholine Methanesulfonate:  A New Selective Rat 5-Hydroxytryptamine_1B Receptor Antagonist

Abstract

In the search for new 5-hydroxytryptamine (5-HT) receptor antagonists it was found that the compound (R)-(+)-2-[[[3-(morpholinomethyl)-2H-chromen-8-yl]oxy] methyl] morpholine methanesulfonate, (R)-25, is a selective rat 5-hydroxytryptamine1B (r5-HT1B) receptor antagonist. The binding profile showed a 13-fold preference for r5-HT1B (Ki = 47 +/- 5 nM; n = 3) vs bovine 5-HT1B (Ki = 630 nM; n = 1) receptors. The compound had very low affinity for other monoaminergic receptors examined. The r5-HT1B receptor antagonism was demonstrated by the potentiation of the K+-stimulated release of [3H]-5-HT from superfused rat brain slices in vitro, an effect that was antagonized by addition of 5-HT to the superfusion fluid. (R)-25 at 20 mg/kg sc enhanced the 5-HT turnover in four rat brain regions (hypothalamus, hippocampus, striatum, and frontal cortex) with about 40% measured as the 5-HTP accumulation after decarboxylase inhibition with 3-hydroxybenzylhydrazine. At 3 mg/kg sc (R)-25 produced a significant increase in the number of wet dog shakes in rats, a 5-HT2A/5-HT2C response that was abolished by depletion of 5-HT after pretreatment with the tryptophan hydroxylase inhibitor p-chlorophenylalanine. These observations show that (R)-25, by inhibiting terminal r5-HT1B autoreceptors, increases the 5-HT turnover and the synaptic concentration of 5-HT.

Analysis of the Role of the 5-HT1B Receptor in Spatial and Aversive Learning in the Rat

“…NAS-181, [R-(+)-2-(3-morpholinomethyl-2H-chromen-8-yl)oxymethylmorpholine methanesulfonate], has been characterized as a potent and selective rat 5-HT 1B receptor antagonist in vitro. The receptor-binding profile of NAS-181 showed a 13-fold preference for the rat (K i ¼ 47 nM) vs the bovine 5-HT 1B receptor (K i ¼ 630 nM), and showed a very low affinity (IC 50 41000 nM) for other serotonergic (5-HT 1A , 5-HT 2A , 5-HT 2C , 5-HT 6 , 5-HT 7 ) as well as adrenergic (a 1 , a 2 , b), dopaminergic (D 1 , D 2 ), and muscarinic receptors (Berg et al, 1998). The effects of NAS-181 on spatial learning and memory were studied using a computerized variant of the Morris WM task (Ö gren et al, 1996).…”

Role of extracellular serotonin levels in the effect of 5-HT1B receptor blockade

“…In the present study, NAS-181, a new selective rodent 5-HT 1B receptor antagonist was used to block 5-HT 1B receptors (Berg et al 1998;Stenfors et al 2000). The aim of the present study was to investigate whether the effects of terminal 5-HT autoreceptor blockade depend on the endogenous tone at 5-HT 1B autoreceptors.…”

Extracellular serotonin in the prefrontal cortex is limited through terminal 5-HT1B autoreceptors: a microdialysis study in knockout mice

“…Research on the role of terminal 5-HT 1B receptors has been impeded by the lack of selective 5-HT 1B receptor antagonists. NAS-181 is a new selective 5-HT 1B receptor antagonist that has been shown to enhance 5-HT metabolism and synthesis in rat brain (Berg et al 1998;Stenfors et al 2000). The development of 5-HT 1B receptor knockout (KO) mice has generated another strategy to study the role of the 5-HT 1B receptor (Saudou et al 1994).…”