In vitro characterization of AR-A000002, a novel 5-hydroxytryptamine1B autoreceptor antagonist

Ahlgren, Charlotte; Eriksson, Anders; Tellefors, Pernilla; Ross, Svante B.; Stenfors, Carina; Malmberg, Åsa

doi:10.1016/j.ejphar.2004.07.067

Cited by 22 publications

(11 citation statements)

References 29 publications

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“…AR-A000002 is a high-affinity 5-HT 1B -selective ligand in cloned guinea pig 5-HT 1B and guinea pig cortical membranes (Ahlgren et al, 2004). In a […”

Section: Discussionmentioning

confidence: 99%

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[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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“…AR-A000002 is a high-affinity 5-HT 1B -selective ligand in cloned guinea pig 5-HT 1B and guinea pig cortical membranes (Ahlgren et al, 2004). In a […”

Section: Discussionmentioning

confidence: 99%

“…Adult Dunkin-Hartley male guinea pigs (180 -260 g) were purchased from Charles River Laboratories (Wilmington, MA (Ahlgren et al, 2004) and for AZD1134 (Horchler et al, 2007) …”

Section: Methodsmentioning

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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“…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%

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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“…NAS-181 [139], S-18127 [140], SB-236057 [141], SB-224289 [143], SB-616234 (138,144,145] and AR-A2 (see Fig. 7) [146][147][148]. Moreover, AR-A2 and elzasonan (CP-448187) have progressed to the clinic for the treatment of anxiety and / or depression.…”

Section: -Ht 1b/d Receptor Antagonism and Sert Inhibitionmentioning

confidence: 95%

5-HT1 Receptor Augmentation Strategies as Enhanced Efficacy Therapeutics for Psychiatric Disorders

Dawson

Bromidge²

2008

CTMC

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Since the initial observations linking 5-HT to psychiatric illness, evidence for a role of 5-HT and, in particular, a decreased brain serotonergic function in the pathology of a plethora of related disorders, has grown. However, it is the role of 5-HT in the pathogenesis of anxiety disorders and depression and the mechanism of action of antidepressants which has received the most attention. Thus enhanced serotonergic neurotransmission has become one of the unifying mechanisms of action of modern day antidepressants/anxiolytics such as monoamine oxidase inhibitors, tricyclic antidepressants, and serotonin reuptake inhibitors. Interestingly all of these treatments are associated with a delay to therapeutic efficacy and in some cases treatment resistance, despite immediate enhancements in serotonergic neurotransmission. The postulated reason for this is the need for temporal neuroplastic changes in the control of serotonergic neurotransmission, and more specifically changes in 5-HT(1) autoreceptor function. Thus significant research has gone into pharmacologically targeting these 5-HT(1) autoreceptors as a means of augmenting the efficacy of current therapeutic mechanisms. Here we will review the rationale behind the various augmentation strategies adopted and the progress made in identifying novel therapeutics for conditions such as depression and anxiety disorders.

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In vitro characterization of AR-A000002, a novel 5-hydroxytryptamine1B autoreceptor antagonist

Cited by 22 publications

References 29 publications

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

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

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

5-HT1 Receptor Augmentation Strategies as Enhanced Efficacy Therapeutics for Psychiatric Disorders

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In vitro characterization of AR-A000002, a novel 5-hydroxytryptamine1B autoreceptor antagonist

Cited by 22 publications

References 29 publications

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

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

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

5-HT1 Receptor Augmentation Strategies as Enhanced Efficacy Therapeutics for Psychiatric Disorders

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Product

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

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