title: (R)-(+)-2-[[[3-(Morpholinomethyl)-2H-chromen-8-yl]oxy]methyl] morpholine methanesulfonate: a new selective rat 5-hydroxytryptamine1B 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.
authors.affiliation: Department of Medicinal Chemistry, Preclinical R&D, Astra Arcus AB, S-151 85 Södertälje, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Berg
authors.forename: L G
authors.initials: LG
authors.lastname: Larsson
authors.forename: L
authors.initials: L
authors.lastname: Rényi
authors.forename: S B
authors.initials: SB
authors.lastname: Ross
authors.forename: S O
authors.initials: SO
authors.lastname: Thorberg
authors.forename: G
authors.initials: G
authors.lastname: Thorell-Svantesson
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D017660:Autoreceptors / Q000037:antagonists & inhibitors*; D001522:Behavior, Animal / Q000187:drug effects; D001578:Benzopyrans / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D066298:In Vitro Techniques; D008024:Ligands; D009025:Morpholines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology
chemical_list: C112429:2-(((3-(morpholinylmethyl)-2H-chromen-8-yl)oxy)methyl)morpholine; D000928:Antidepressive Agents; D017660:Autoreceptors; D001578:Benzopyrans; D008024:Ligands; D009025:Morpholines; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D012701:Serotonin