Pharmacology of a novel selective 5-hydroxytryptamine 1B receptor antagonist, AR-A000002

Abstract

The terminal 5-HT(1B) autoreceptors have attracted great pharmacological interest since they are potential targets for compounds modifying serotonergic neurotransmission. In the present work the in vivo biochemical properties of AR-A000002 ((R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide), a novel selective 5-HT(1B) receptor antagonist, are reported. The effects of AR-A000002 on: 5-HT metabolism was measured as the ratio between 5-HIAA and 5-HT concentrations in different brain regions; 5-HT synthesis was measured as the accumulation of 5-HTP after inhibition of the aromatic amino acid decarboxylase activity with m-hydroxybenzylhydrazine (NSD1015); 5-HT release was measured using the microdialysis technique. 5-HT, 5-HIAA and 5-HTP concentrations were analyzed using high power liquid chromatography (HPLC) with electrochemical detection. AR-A000002 significantly enhanced 5-HT metabolism (5-HIAA/5-HT ratio) and 5-HT synthesis in guinea pig brain in the dose range 0.9-18 mg/kg s.c. (ED(50)=1 mg/kg s.c. in the four brain regions examined) with maximal effect seen after 2-4 h. AR-A000002 (9 mg/kg s.c.) significantly increased the extracellular concentrations of 5-HT and 5-HIAA by 20% in the guinea pig frontal cortex, measured with the in vivo microdialysis technique in freely moving guinea pigs. AR-A000002 (9 mg/kg s.c.) in combination with the 5-HT uptake inhibitor citalopram (5 mg/kg s.c.) increased the extracellular 5-HT concentration in guinea pig frontal cortex from 250 to 400% of the basal level. Citalopram alone decreased the extracellular 5-HIAA levels to 70% of the basal value. AR-A000002 counteracted the citalopram-induced decrease in 5-HIAA. Since the basal level of extracellular 5-HIAA was 160 times higher than that of 5-HT the 20% increase in 5-HIAA concentrations indicates that only a few percent of the exocytotically released 5-HT from the nerve terminals reached the extracellular space when the re-uptake mechanism was intact. The results also show that the terminal 5-HT(1B) autoreceptors are tonically activated under drug-free as well as citalopram conditions. The increase in plasma level of cortisol after AR-A000002 administration may indicate stimulation of post-synaptic 5-HT receptors. AR-A000002 also blocked 5-HT(1B) agonist-induced (CP-135,807) decrease in 5-HT metabolism and hypothermia (ED(50)=1 mg/kg s.c.), thus indicating competition between these two drugs. It is concluded that AR-A000002 is a 5-HT(1B) receptor antagonist that enhances the serotonergic neurotransmission in guinea pig brain.

Dose-dependent binding of AZD3783 to brain 5-HT1B receptors in non-human primates and human subjects: a positron emission tomography study with [11C]AZ10419369

“…K i,plasma AZD3783 plasma concentration required for half-maximum receptor occupancy binding to the receptor and residual binding of endogenous 5-HT released after AZD3783 administration. However, increases in endogenous 5-HT observed with 5-HT 1B antagonists in microdialysis studies are moderate (0.2-to 2-fold; Stenfors et al 2004;Dawson et al 2006) when compared to the marked elevation in 5-HT release induced by fenfluramine (20-to 35-fold; Udo de Haes et al 2006). Future studies with [ 11 C]AZ10419369 and a pharmacological manipulation that induce more moderate elevations in endogenous 5-HT levels are required to clarify the contribution of residual binding of endogenous 5-HT to the occupancy measured with AZD3783.…”

“…As shown with the microdialysis technique, centrally active 5-HT 1B receptor antagonists increase extracellular levels of 5-HT (Stenfors et al 2004;Dawson et al 2006). It may therefore be assumed that elevation in 5-HT levels in response to AZD3783 administration may reduce radioligand binding to brain 5-HT 1B receptors.…”

“…Since binding of 5-HT to the 5-HT 1B autoreceptor reduces synaptic release of 5-HT, it has been suggested that treatment with a 5-HT 1B receptor antagonist may provide a more rapid increase in brain 5-HT concentrations and an earlier onset of action compared to the currently available treatment alternatives (Moret and Briley 2000). Indeed, in animal models of depression, antagonists at the 5-HT 1B receptor have been demonstrated to enhance 5-HT function (Stenfors et al 2004;Dawson et al 2006) and to show antidepressant-like effects (Hudzik et al 2003a, b). The clinical utility of 5-HT 1B receptor antagonists remains, however, to be evaluated.…”

Preclinical Pharmacology and Pharmacokinetics of AZD3783, a Selective 5-Hydroxytryptamine 1B Receptor Antagonist

“…This mechanism also has the potential to provide a rapid onset of clinical efficacy without the liabilities associated with SSRIs (Moret and Briley, 2000;Slassi, 2002). Animal models such as serotonin agonist-induced guinea pig hypothermia (Maj et al, 1988) and guinea pig pup separation-induced vocalization (Hagan et al, 1997;Hudzik et al, 2003;Stenfors et al, 2004;Dawson et al, 2006) were developed to screen and evaluate the pharmacology of serotonergic agents such as 5-HT 1B receptor antagonists. Selective 5-HT 1B antagonists such as (R)-N- [5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide (AR-A000002) (Hudzik et al, 2003) and 1-[6-(cis-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-5-methoxyindol-1-yl]-1-[2Ј-methyl-4Ј-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methanone hydrochloride (SB-616234-A) (Dawson et al, 2006) have been shown to elevate serotonergic neurotransmission in vivo and exhibit effects indicative of antidepressant and anxiolytic properties in animals.…”

The guinea pig forced swim test as a new behavioral despair model to characterize potential antidepressants

“…Rats and mice are being used for almost all models. However, potential new drug targets often show species differences (Oksenberg et al 1992;Pradier et al 1995) and pharmacology, which differs between murids and humans (Beresford et al 1991;Stenfors et al 2004). In many cases, guinea pig receptors display higher homology and pharmacology more similar to their human counterparts as compared to murid receptors.…”