BRL 46470A: a highly potent, selective and long acting 5-HT3 receptor antagonist with anxiolytic-like properties

  title={BRL 46470A: a highly potent, selective and long acting 5-HT3 receptor antagonist with anxiolytic-like properties},
  author={Thomas P Blackburn and Gordon Smith Baxter and Guy A. Kennett and Frank D. King and David C. Piper and Graham J Sanger and D. R. Thomas and Neil Upton and Martyn D. Wood},
The novel 5-HT3 antagonist, BRL 46470A (endo-N-(8-methyl-8-azabicyclo [3.2.1]oct-3-yl)2,3-dihydro-3,3 dimethyl-indole-1-carboxamide, hydrochloride), has been investigated in a series of in vitro and in vivo tests, including the effect of the drug in models of anxiolysis. In classical tests for 5-HT3 receptor antagonism, BRL 46470A was shown to antagonise 5-HT3 mediated responses in the guinea-pig ileum [pA2 8.3±0.5, slope 0.98±0.20, mean±SEM (5)], the rabbit isolated heart (pA2 10.1±0.1, slope… 

2-(4-substituted piperazin-1-yl)-1,8-naphthyridine-3-carboxylic acids: novel 5-HT3 receptor antagonists with anxiolytic-like activity in rodent behavioral models.

The aim of this study was to investigate the anxiolytic potential of a series of novel carboxylic acid based 1,8 naphthyridines as 5-HT3 receptor antagonists. The pA2 values of all the compounds were

Pharmacological evaluation of novel 5-HT3 receptor antagonist, QCM-13 (N-cyclohexyl-3-methoxyquinoxalin-2-carboxamide) as anti-anxiety agent in behavioral test battery

The results suggest that QCM-13 can be a potential therapeutic candidate for the management of anxiety-like disorders and combination doses of novel 5-HT3 receptor antagonist with standard anxiolytics may improve therapeutic efficacy.

Pharmacological Effects of Lu AA21004: A Novel Multimodal Compound for the Treatment of Major Depressive Disorder

In vivo, Lu AA21004 mediates its pharmacological effects via two pharmacological modalities: SERT inhibition and 5-HT receptor modulation and this results in enhanced release of several neurotransmitters and antidepressant- and anxiolytic-like profiles at doses for which targets in addition to the SERT are occupied.

5-HT1C receptor antagonists have anxiolytic-like actions in the rat social interaction model

  • G. Kennett
  • Biology, Psychology
  • 2005
The results imply that the observed anxiolytic effects of the drugs are likely to be mediated by 5-HT1C receptor blockade.

Profile of action of 5-HT3 receptor antagonists, ondansetron and WAY 100289, in the elevated plus-maze test of anxiety of mice

It is suggested that the large within- and between-test variability observed with these compounds may indicate an action on mechanisms other than anxiety, as well as the enigmatic effects of 5-HT3 receptor antagonists in animal models of anxiety.

Dehydrogenation of the Indoline-Containing Drug 4-Chloro-N-(2-methyl-1-indolinyl)-3-sulfamoylbenzamide (Indapamide) by CYP3A4: Correlation with in Silico Predictions

Several indAPamide metabolic pathways in vitro with human liver microsomes and recombinant CYP3A4 that include the dehydrogenation of indapamide to its corresponding indole form, and also hydroxylation and epoxidation metabolites, as characterized by liquid chromatography/mass spectrometry are identified.

A Brief Summary for 5-HT Receptors

The comprehensive information on 5-HT receptors is summarized in a concise summary with detailed references, which may help the readers for further information excavation.

The Non-Antiemetic Uses of Serotonin 5-HT3 Receptor Antagonists

No clinical studies have yet clearly demonstrated the usefulness of 5-HT3 receptor antagonists in the treatment of CNS disorders, and further research would be useful in confirming the effectiveness, or otherwise, of this group of compounds.

The Role of 5-HT2C Receptors in the Pathophysiology and Treatment of Depression

This chapter aims to summarize the four lines of evidence for the involvement of 5-HT2C receptors in pathophysiology and treatment of depression.



MDL 72222: a potent and highly selective antagonist at neuronal 5-hydroxytryptamine receptors

  • J. Fozard
  • Biology
    Naunyn-Schmiedeberg's Archives of Pharmacology
  • 2004
MDL 72222 is the first reported selective and potent antagonist of responses mediated through the 5-HT receptors present on the terminal sympathetic neurones of the rabbit heart and on the neurones subserving the afferent limb of the Bezold-Jarisch reflex.

Characterization of the binding of [3H]L-365,260: a new potent and selective brain cholecystokinin (CCK-B) and gastrin receptor antagonist radioligand.

The data indicates that [3H]L-365,260 represents a new potent nonpeptide antagonist radioligand suitable for the study of brain CCK-B and gastrin receptors.

Identification and distribution of 5-HT3 receptors in rat brain using radioligand binding

Direct evidence for the existence of 5-HT3 receptors in rat brain tissue and their distribution is reported, based on high affinity binding of the potent 5- HT3 receptor antagonist 3H-GR65630 to homogenates of rat entorhinal cortex.

5-Methoxytryptamine and 2-methyl-5-hydroxytryptamine-induced desensitization as a discriminative tool for the 5-HT3 and putative 5-HT4 receptors in guinea pig ileum

It is concluded that 5-methoxytryptamine and 2-methyl-5-HT can be utilized as selective probes to discriminate the putative 5-HT4 receptor from the 5- HT3 receptor in guinea pig ileum.

5-HT1D receptors in guinea-pig and pigeon brain

It is suggested that 5-HT1D sites may be present in the brain of the majority of vertebrate species located higher than the sauropside-mammalian divergence in the phylogenic tree, whereas 5- HT1B sites are only found in some rodents.

Anxiogenic-like effects of mCPP and TFMPP in animal models are opposed by 5-HT1C receptor antagonists.

Characterization of the binding of [3H]-(+/-)-L-364,718: a new potent, nonpeptide cholecystokinin antagonist radioligand selective for peripheral receptors.

Data indicate that [3H]-(+/-)-L-364,718 represents a new potent nonpeptide antagonist radioligand for the study of peripheral CCK receptors which may allow differentiation of agonist and antagonist interactions.

5-Hydroxytryptamine4 receptors mediate relaxation of the rat oesophageal tunica muscularis mucosae

Concentration-effect curves to 5-HT were not affected by tetrodotoxin or indomethacin, sugesting that 5- HT-induced relaxation of the tunica muscularis mucosae was mediated via a postjunctional receptor, independent of endogenous prostanoids.