Characterisation of the selective 5-HT1B receptor antagonist SB-616234-A (1-[6-(cis-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-5-methoxyindol-1-yl]-1-[2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methanone hydrochloride): In vivo neurochemical and behavioural evidence of anxiolytic/antidepressant activity

Dawson, Lee A.; Hughes, Zoë A.; Starr, Kathryn R.; Storey, James D.; Bettelini, L.; Bacchi, Fabrizio; Arban, Roberto; Poffe, Alessandro; Melotto, Sergio; Hagan, James J.; Price, Gary

doi:10.1016/j.neuropharm.2006.01.010

Cited by 39 publications

(27 citation statements)

References 44 publications

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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“…The presynaptic 5-HT 1B autoreceptor also regulates 5-HT release, so it has been considered as an alternative target to 5-HT reuptake transporters for antidepressants (Gaster et al, 1998;Hillegaart and Ahlenius, 1998;Roberts et al, 2001;Ahlgren et al, 2004;Dawson et al, 2006). 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).…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

“…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 discovery of selective, high-affinity 5-HT 1B compounds made it possible to develop 5-HT 1B -specific ligands for positron emission tomography (PET) to obtain noninvasive quantification of specific binding to the receptor in brain (Pierson et al, 2008;Nabulsi et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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

Zhang¹,

Zhou²,

Wang³

et al. 2011

J Pharmacol Exp Ther

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The preclinical pharmacology and pharmacokinetic properties of (2R)-6-methoxy-8-(4-methylpiperazin-1-yl)-N-(4-morpholin-4-ylphenyl)chromane-2-carboxamide (AZD3783), a potent 5-hydroxytryptamine 1B (5-HT 1B ) receptor antagonist, were characterized as part of translational pharmacokinetic/pharmacodynamic hypothesis testing in human clinical trials. The affinity of AZD3783 to the 5-HT 1B receptor was measured in vitro by using membrane preparations containing recombinant human or guinea pig 5-HT 1B receptors and in native guinea pig brain tissue. In vivo antagonist potency of AZD3783 for the 5HT 1B receptor was investigated by measuring the blockade of 5-HT 1B agonist-induced guinea pig hypothermia. The anxiolytic-like potency was assessed using the suppression of separation-induced vocalization in guinea pig pups. The affinity of AZD3783 for human and guinea pig 5-HT 1B receptor (K i , 12.5 and 11.1 nM, respectively) was similar to unbound plasma EC 50 values for guinea pig receptor occupancy (11 nM) and reduction of agonist-induced hypothermia (18 nM) in guinea pig. Active doses of AZD3783 in the hypothermia assay were similar to doses that reduced separation-induced vocalization in guinea pig pups. AZD3783 demonstrated favorable pharmacokinetic properties. The predicted pharmacokinetic parameters (total plasma clearance, 6.5 ml/min/kg; steady-state volume of distribution, 6.4 l/kg) were within 2-fold of the values observed in healthy male volunteers after a single 20-mg oral dose. This investigation presents a direct link between AZD3783 in vitro affinity and in vivo receptor occupancy to preclinical disease model efficacy. Together with predicted human pharmacokinetic properties, we have provided a model for the quantitative translational pharmacology of AZD3783 that increases confidence in the optimal human receptor occupancy required for antidepressant and anxiolytic effects in patients.

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“…Blocking 5-HT 1B autoreceptors with a selective ligand increases extracellular levels of 5-HT and has an additive effect on 5-HT increase when combined with selective serotonin reuptake inhibitors, suggesting the antidepressive potential of a 5-HT 1B drug (Matzen et al, 2000;Smagin et al, 2003). Indeed, drugs targeting 5-HT 1B receptors have shown efficacy in animal models of depression and anxiety (Hudzik et al, 2003a,b;Dawson et al, 2006). In humans, selective serotonin reuptake inhibitors usually have up to 4 weeks of delayed antidepressive effect attributed to gradual down-regulation and slow desensitization of 5-HT 1B autoreceptors.…”

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confidence: 99%

[N-methyl-³H₃]AZ10419369 Binding to the 5-HT_1BReceptor: In Vitro Characterization and in Vivo Receptor Occupancy

Maier¹,

Sobotka-Briner²,

Ding³

et al. 2009

J Pharmacol Exp Ther

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Radiotracers suitable for positron emission tomography studies often serve as preclinical tools for in vivo receptor occupancy. The serotonin 1B receptor (5-HT 1B ) subtype is a pharmacological target used to discover treatments for various psychiatric and neurological disorders. In psychiatry, 5-HT 1B antagonists may provide novel therapeutics for depression and anxiety. We report on the in vitro and in vivo evaluation of tritiated 5-methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylicacid (4-morpholin-4-yl-phenyl)-amide ([N-methyl- (Hoyer et al., 2002). The serotonin 1B receptor (5-HT 1B ) subtype has been implicated in normal physiological functions and behavior and in neurological and psychiatric disorders, such as diseases of locomotion, migraine, drug abuse, aggressive behavior, anxiety, and depression [Moret and Briley, 2000;Svenningsson et al., 2006; for review, see Sari (2004)]. 5-HT 1B receptors modulate synaptic release of sero-M.D., M.E.Po., Q.J., and G.H. contributed equally to this work. Article, publication date, and citation information can be found at

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Cited by 39 publications

References 44 publications

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

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

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

[N-methyl-³H₃]AZ10419369 Binding to the 5-HT_1BReceptor: In Vitro Characterization and in Vivo Receptor Occupancy

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Cited by 39 publications

References 44 publications

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

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

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

[N-methyl-3H3]AZ10419369 Binding to the 5-HT1BReceptor: In Vitro Characterization and in Vivo Receptor Occupancy

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[N-methyl-³H₃]AZ10419369 Binding to the 5-HT_1BReceptor: In Vitro Characterization and in Vivo Receptor Occupancy