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Arlene D. Stark,
Shaun Jordan,
Kelly A. Allers,
Robert L. Bertekap,
Ruoyan Chen,
Tanaz Mistry Kannan,
Thaddeus F. Molski,
Frank D. Yocca,
Trevor Sharp,
Tetsuro Kikuchi,
Kevin D. Burris
[show abstract]
[hide abstract]
ABSTRACT: BackgroundAripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinone) is a novel antipsychotic with a mechanism of action that differs from current typical and atypical antipsychotics.
Aripiprazole interacts with a range of receptors, including serotonin [5-hydroxytryptamine (5-HT)] and dopamine receptors.
Materials and methodsThis study examined aripiprazole’s interactions with 5-HT systems in vitro and in vivo to further clarify its pharmacologic
properties.
ResultsAripiprazole produced increases in [35S]GTPγS binding to rat hippocampal membranes. Its potency (pEC50 = 7.2) was similar to that of ziprasidone (7.1) and greater than that of 5-HT (6.7) and buspirone (6.4), a 5-HT1A-receptor partial agonist, whereas its intrinsic activity was similar to that of ziprasidone and buspirone. The stimulatory
effect of aripiprazole was blocked by WAY-100635, a 5-HT1A-receptor antagonist. In in vivo electrophysiology studies, aripiprazole produced a dose-related reduction in the firing
rate of 5-HT-containing dorsal raphe neurons in rats, which was both prevented and reversed by WAY-100635 administration.
Aripiprazole showed a high affinity for human 5-HT1A receptors (K
i = 4.2nM) using parietal cortex membrane preparations. In membranes from cells expressing human recombinant receptors, aripiprazole
bound with high affinity to 5-HT2A receptors (K
i = 3.4nM), moderate affinity to 5-HT2C (K
i = 15nM) and 5-HT7 (K
i = 39nM) receptors, and low affinity to 5-HT6 receptors (K
i = 214nM) and 5-HT transporter (K
i = 98nM). In addition, aripiprazole potently blocked 5-HT2A-receptor-mediated increases in intracellular Ca2+ levels in a rat pituitary cell line (IC50 = 11nM).
DiscussionThese results support a partial agonist activity for aripiprazole at 5-HT1A receptors in vitro and in vivo, and suggest important interactions with other 5-HT-receptor subtypes. This receptor activity
profile may contribute to the antipsychotic activity of aripiprazole in humans.
Psychopharmacologia 04/2012; 190(3):373-382. · 4.08 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The pharmacokinetics and in vivo potency of 6-hydroxybuspirone (6-OH-buspirone), a major metabolite of buspirone, were investigated. The plasma clearance (47.3 +/- 3.5 ml/min/kg), volume of distribution (2.6 +/- 0.3 l/kg), and half-life (1.2 +/- 0.2 h) of 6-OH-buspirone in rats were similar to those for buspirone. Bioavailability was higher for 6-OH-buspirone (19%) compared with that for buspirone (1.4%). After intravenous infusions to steady-state levels in plasma, 6-OH-buspirone and buspirone increased 5-hydroxytryptamine (HT)(1A) receptor occupancy in a concentration-dependent manner with EC(50) values of 1.0 +/- 0.3 and 0.38 +/- 0.06 microM in the dorsal raphe and 4.0 +/- 0.6 and 1.5 +/- 0.3 microM in the hippocampus, respectively. Both compounds appeared to be approximately 4-fold more potent in occupying presynaptic 5-HT(1A) receptors in the dorsal raphe than the postsynaptic receptors in the hippocampus. Oral dosing of buspirone in rats resulted in exposures (area under the concentration-time profile) of 6-OH-buspirone and 1-(2-pyrimidinyl)-piperazine (1-PP), another major metabolite of buspirone, that were approximately 12 (6-OH-buspirone)- and 49 (1-PP)-fold higher than the exposure of the parent compound. As a whole, these preclinical data suggest that 6-OH-buspirone probably contributes to the clinical efficacy of buspirone as an anxiolytic agent.
Drug Metabolism and Disposition 09/2007; 35(8):1387-92. · 3.73 Impact Factor
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Arlene D Stark,
Shaun Jordan,
Kelly A Allers,
Robert L Bertekap,
Ruoyan Chen,
Tanaz Mistry Kannan,
Thaddeus F Molski,
Frank D Yocca,
Trevor Sharp,
Tetsuro Kikuchi,
Kevin D Burris
[show abstract]
[hide abstract]
ABSTRACT: Aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinone) is a novel antipsychotic with a mechanism of action that differs from current typical and atypical antipsychotics. Aripiprazole interacts with a range of receptors, including serotonin [5-hydroxytryptamine (5-HT)] and dopamine receptors.
This study examined aripiprazole's interactions with 5-HT systems in vitro and in vivo to further clarify its pharmacologic properties.
Aripiprazole produced increases in [(35)S]GTPgammaS binding to rat hippocampal membranes. Its potency (pEC(50) = 7.2) was similar to that of ziprasidone (7.1) and greater than that of 5-HT (6.7) and buspirone (6.4), a 5-HT(1A)-receptor partial agonist, whereas its intrinsic activity was similar to that of ziprasidone and buspirone. The stimulatory effect of aripiprazole was blocked by WAY-100635, a 5-HT(1A)-receptor antagonist. In in vivo electrophysiology studies, aripiprazole produced a dose-related reduction in the firing rate of 5-HT-containing dorsal raphe neurons in rats, which was both prevented and reversed by WAY-100635 administration. Aripiprazole showed a high affinity for human 5-HT(1A) receptors (K (i) = 4.2 nM) using parietal cortex membrane preparations. In membranes from cells expressing human recombinant receptors, aripiprazole bound with high affinity to 5-HT(2A) receptors (K (i) = 3.4 nM), moderate affinity to 5-HT(2C) (K (i) = 15 nM) and 5-HT(7) (K (i) = 39 nM) receptors, and low affinity to 5-HT(6) receptors (K (i) = 214 nM) and 5-HT transporter (K (i) = 98 nM). In addition, aripiprazole potently blocked 5-HT(2A)-receptor-mediated increases in intracellular Ca(2+) levels in a rat pituitary cell line (IC(50) = 11 nM).
These results support a partial agonist activity for aripiprazole at 5-HT(1A) receptors in vitro and in vivo, and suggest important interactions with other 5-HT-receptor subtypes. This receptor activity profile may contribute to the antipsychotic activity of aripiprazole in humans.
Psychopharmacologia 03/2007; 190(3):373-82. · 4.08 Impact Factor
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Derek J Denhart,
Ashok V Purandare,
John D Catt,
H Dalton King,
Aiming Gao,
Jeffrey A Deskus,
Michael A Poss, Arlene D Stark,
John R Torrente,
Graham Johnson,
Ronald J Mattson
[show abstract]
[hide abstract]
ABSTRACT: The present studies have identified a series of diaminopyrimidines and diaminopyridines as novel 5-HT(7) receptor ligands. Three regiosiomeric classes of pyrimidines and four regioisomeric classes of pyridines were synthesized and analyzed for binding to the 5-HT(7) receptor. The 5-HT(7) binding affinities of different regioisomers show clearly the structure-activity relationship with position of ring nitrogens.
Bioorganic & Medicinal Chemistry Letters 09/2004; 14(16):4249-52. · 2.55 Impact Factor
