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Aaron Janowsky - One of the best experts on this subject based on the ideXlab platform.
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Characteristics of Drug Interactions with Recombinant Biogenic Amine Transporters Expressed in the Same
2016Co-Authors: Cell Type, Amy J Eshleman, Marya Carmolli, Medhane G Cumbay, Carey R Martens, Kim A Neve, Aaron JanowskyAbstract:We characterized the effects of drugs on the Uptake of [3H]neu-rotransmitter by and the binding of [125I](3b-(4-iodophenyl)tro-pane-2b-carboxylic acid methyl ester ([125I]RTI-55) to the re-combinant human dopamine (hDAT), serotonin (hSERT), or norepinephrine (hNET) transporters stably expressed in human embryonic kidney 293 cells. RTI-55 had similar affinity for the hDAT and hSERT and lower affinity for hNET (Kd 5 1.83, 0.98, and 12.1 nM, respectively). Kinetic analysis of [125I]RTI-55 bind-ing indicated that the dissociation rate (k21) was significantly lower for hSERT and the association rate (k11) was significantly lower for hNET compared with the hDAT. The potency of drugs at blocking [3H]Neurotransmitter Uptake was highly correlated with potency at blocking radioligand binding for hDAT and hSERT. Substrates were more potent at the inhibition of [3H]Neurotransmitter Uptake than radioligand binding. The po-tency of drugs was highly correlated between displacement of [3H]nisoxetine (Kd 5 6.0 nM) and [ 125I]RTI-55 from the hNET, suggesting that these radioligands recognize similar sites on the transporter protein. The correlation observed between in-hibitory potency for Uptake and binding of either ligand at the hNET was lower than correlations between Uptake and binding for hDAT and hSERT. The present results indicate that the cocaine analog [125I]RTI-55 has unique binding properties at each of the transporters and that the use of recombinant trans-porters expressed by a single cell type can provide a powerful screening tool for drugs interacting with biogenic amine trans-porters, such as possible cocaine antagonists. Sodium- and chloride-sensitive biogenic amine transport-ers are the major mechanism for terminating the neurotrans-mission of dopamine (DA), norepinephrine (NE), and seroto
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Pharmacological Profile of the “Triple” Monoamine Neurotransmitter Uptake Inhibitor, DOV 102,677
Cellular and Molecular Neurobiology, 2006Co-Authors: Piotr Popik, Martyna Krawczyk, Krystyna Golembiowska, Gabriel Nowak, Aaron Janowsky, Phil Skolnick, Arnold Lippa, Anthony S. BasileAbstract:1. The molecular and behavioral pharmacology of DOV 102,677 is characterized. 2. This characterization was performed using radioligand binding and Neurotransmitter Uptake assays targeting the monoamine Neurotransmitter receptors. In addition, the effects of DOV 102,677 on extracellular Neurotransmitter levels were investigated using in vivo microdialysis. Finally, the effects of DOV 102,677 in the forced swim test, locomotor function, and response to prepulse inhibition was investigated. 3. DOV 102,677 is a novel, “triple” Uptake inhibitor that suppresses [^3H]dopamine (DA), [^3H]norepinephrine (NE) and [^3H]serotonin (5-HT) Uptake by recombinant human transporters with IC_50 values of 129, 103 and 133 nM, respectively. Radioligand binding to the dopamine (DAT), norepinephrine (NET), and serotonin (SERT) transporters is inhibited with k _i values of 222, 1030, and 740 nM, respectively. DOV 102,677 (20 mg/kg IP) increased extracellular levels of DA and 5-HT in the prefrontal cortex to 320 and 280% above baseline 100 min after administration. DA levels were stably increased for the duration (240 min) of the study, but serotonin levels declined to baseline by 200 min after administration. NE levels increased linearly to a maximum of 348% at 240 min post-dosing. Consistent with these increases in NE levels, the density of β-adrenoceptors was selectively decreased in the cortex of rats treated with DOV 102,677 (20 mg/kg per day, PO, 35 days). 4. DOV 102,677 dose-dependently reduced the amount of time spent immobile by rats in the forced swim test, a model predictive of antidepressant activity, with a minimum effective dose (MED) of 20 mg/kg and a maximal efficacy comparable to imipramine. This decrease in immobility time did not appear to result from increased motor activity. Further, DOV 102,677 was as effective as methylphenidate in reducing the amplitude of the startle response in juvenile mice, without notably altering motor activity. 5. In summary, DOV 102,677 is an orally active, “balanced” inhibitor of DAT, NET and SERT with therapeutic versatility in treating neuropsychiatric disorders beyond depression.
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Pharmacological profile of the "triple" monoamine Neurotransmitter Uptake inhibitor, DOV 102,677.
Cellular and molecular neurobiology, 2006Co-Authors: Piotr Popik, Martyna Krawczyk, Krystyna Golembiowska, Gabriel Nowak, Aaron Janowsky, Phil Skolnick, Arnold Lippa, Anthony S. BasileAbstract:1. The molecular and behavioral pharmacology of DOV 102,677 is characterized. 2. This characterization was performed using radioligand binding and Neurotransmitter Uptake assays targeting the monoamine Neurotransmitter receptors. In addition, the effects of DOV 102,677 on extracellular Neurotransmitter levels were investigated using in vivo microdialysis. Finally, the effects of DOV 102,677 in the forced swim test, locomotor function, and response to prepulse inhibition was investigated.3. DOV 102,677 is a novel, "triple" Uptake inhibitor that suppresses [(3)H]dopamine (DA), [(3)H]norepinephrine (NE) and [(3)H]serotonin (5-HT) Uptake by recombinant human transporters with IC(50) values of 129, 103 and 133 nM, respectively. Radioligand binding to the dopamine (DAT), norepinephrine (NET), and serotonin (SERT) transporters is inhibited with k (i) values of 222, 1030, and 740 nM, respectively. DOV 102,677 (20 mg/kg IP) increased extracellular levels of DA and 5-HT in the prefrontal cortex to 320 and 280% above baseline 100 min after administration. DA levels were stably increased for the duration (240 min) of the study, but serotonin levels declined to baseline by 200 min after administration. NE levels increased linearly to a maximum of 348% at 240 min post-dosing. Consistent with these increases in NE levels, the density of beta-adrenoceptors was selectively decreased in the cortex of rats treated with DOV 102,677 (20 mg/kg per day, PO, 35 days). 4. DOV 102,677 dose-dependently reduced the amount of time spent immobile by rats in the forced swim test, a model predictive of antidepressant activity, with a minimum effective dose (MED) of 20 mg/kg and a maximal efficacy comparable to imipramine. This decrease in immobility time did not appear to result from increased motor activity. Further, DOV 102,677 was as effective as methylphenidate in reducing the amplitude of the startle response in juvenile mice, without notably altering motor activity. 5. In summary, DOV 102,677 is an orally active, "balanced" inhibitor of DAT, NET and SERT with therapeutic versatility in treating neuropsychiatric disorders beyond depression.
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characteristics of drug interactions with recombinant biogenic amine transporters expressed in the same cell type
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: Amy J Eshleman, Marya Carmolli, Medhane G Cumbay, Carey R Martens, Kim A Neve, Aaron JanowskyAbstract:We characterized the effects of drugs on the Uptake of [3H]Neurotransmitter by and the binding of [125I](3β-(4-iodophenyl)tropane-2β-carboxylic acid methyl ester ([125I]RTI-55) to the recombinant human dopamine (hDAT), serotonin (hSERT), or norepinephrine (hNET) transporters stably expressed in human embryonic kidney 293 cells. RTI-55 had similar affinity for the hDAT and hSERT and lower affinity for hNET ( K d = 1.83, 0.98, and 12.1 nM, respectively). Kinetic analysis of [125I]RTI-55 binding indicated that the dissociation rate ( k −1) was significantly lower for hSERT and the association rate ( k +1) was significantly lower for hNET compared with the hDAT. The potency of drugs at blocking [3H]Neurotransmitter Uptake was highly correlated with potency at blocking radioligand binding for hDAT and hSERT. Substrates were more potent at the inhibition of [3H]Neurotransmitter Uptake than radioligand binding. The potency of drugs was highly correlated between displacement of [3H]nisoxetine ( K d = 6.0 nM) and [125I]RTI-55 from the hNET, suggesting that these radioligands recognize similar sites on the transporter protein. The correlation observed between inhibitory potency for Uptake and binding of either ligand at the hNET was lower than correlations between Uptake and binding for hDAT and hSERT. The present results indicate that the cocaine analog [125I]RTI-55 has unique binding properties at each of the transporters and that the use of recombinant transporters expressed by a single cell type can provide a powerful screening tool for drugs interacting with biogenic amine transporters, such as possible cocaine antagonists.
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Characteristics of drug interactions with recombinant biogenic amine transporters expressed in the same cell type.
The Journal of pharmacology and experimental therapeutics, 1999Co-Authors: Amy J Eshleman, Marya Carmolli, Medhane G Cumbay, Carey R Martens, Kim A Neve, Aaron JanowskyAbstract:We characterized the effects of drugs on the Uptake of [3H]Neurotransmitter by and the binding of [125I](3beta-(4-iodophenyl)tropane-2beta-carboxylic acid methyl ester ([125I]RTI-55) to the recombinant human dopamine (hDAT), serotonin (hSERT), or norepinephrine (hNET) transporters stably expressed in human embryonic kidney 293 cells. RTI-55 had similar affinity for the hDAT and hSERT and lower affinity for hNET (Kd = 1. 83, 0.98, and 12.1 nM, respectively). Kinetic analysis of [125I]RTI-55 binding indicated that the dissociation rate (k-1) was significantly lower for hSERT and the association rate (k+1) was significantly lower for hNET compared with the hDAT. The potency of drugs at blocking [3H]Neurotransmitter Uptake was highly correlated with potency at blocking radioligand binding for hDAT and hSERT. Substrates were more potent at the inhibition of [3H]Neurotransmitter Uptake than radioligand binding. The potency of drugs was highly correlated between displacement of [3H]nisoxetine (Kd = 6.0 nM) and [125I]RTI-55 from the hNET, suggesting that these radioligands recognize similar sites on the transporter protein. The correlation observed between inhibitory potency for Uptake and binding of either ligand at the hNET was lower than correlations between Uptake and binding for hDAT and hSERT. The present results indicate that the cocaine analog [125I]RTI-55 has unique binding properties at each of the transporters and that the use of recombinant transporters expressed by a single cell type can provide a powerful screening tool for drugs interacting with biogenic amine transporters, such as possible cocaine antagonists.
Anthony S. Basile - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological Profile of the “Triple” Monoamine Neurotransmitter Uptake Inhibitor, DOV 102,677
Cellular and Molecular Neurobiology, 2006Co-Authors: Piotr Popik, Martyna Krawczyk, Krystyna Golembiowska, Gabriel Nowak, Aaron Janowsky, Phil Skolnick, Arnold Lippa, Anthony S. BasileAbstract:1. The molecular and behavioral pharmacology of DOV 102,677 is characterized. 2. This characterization was performed using radioligand binding and Neurotransmitter Uptake assays targeting the monoamine Neurotransmitter receptors. In addition, the effects of DOV 102,677 on extracellular Neurotransmitter levels were investigated using in vivo microdialysis. Finally, the effects of DOV 102,677 in the forced swim test, locomotor function, and response to prepulse inhibition was investigated. 3. DOV 102,677 is a novel, “triple” Uptake inhibitor that suppresses [^3H]dopamine (DA), [^3H]norepinephrine (NE) and [^3H]serotonin (5-HT) Uptake by recombinant human transporters with IC_50 values of 129, 103 and 133 nM, respectively. Radioligand binding to the dopamine (DAT), norepinephrine (NET), and serotonin (SERT) transporters is inhibited with k _i values of 222, 1030, and 740 nM, respectively. DOV 102,677 (20 mg/kg IP) increased extracellular levels of DA and 5-HT in the prefrontal cortex to 320 and 280% above baseline 100 min after administration. DA levels were stably increased for the duration (240 min) of the study, but serotonin levels declined to baseline by 200 min after administration. NE levels increased linearly to a maximum of 348% at 240 min post-dosing. Consistent with these increases in NE levels, the density of β-adrenoceptors was selectively decreased in the cortex of rats treated with DOV 102,677 (20 mg/kg per day, PO, 35 days). 4. DOV 102,677 dose-dependently reduced the amount of time spent immobile by rats in the forced swim test, a model predictive of antidepressant activity, with a minimum effective dose (MED) of 20 mg/kg and a maximal efficacy comparable to imipramine. This decrease in immobility time did not appear to result from increased motor activity. Further, DOV 102,677 was as effective as methylphenidate in reducing the amplitude of the startle response in juvenile mice, without notably altering motor activity. 5. In summary, DOV 102,677 is an orally active, “balanced” inhibitor of DAT, NET and SERT with therapeutic versatility in treating neuropsychiatric disorders beyond depression.
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Pharmacological profile of the "triple" monoamine Neurotransmitter Uptake inhibitor, DOV 102,677.
Cellular and molecular neurobiology, 2006Co-Authors: Piotr Popik, Martyna Krawczyk, Krystyna Golembiowska, Gabriel Nowak, Aaron Janowsky, Phil Skolnick, Arnold Lippa, Anthony S. BasileAbstract:1. The molecular and behavioral pharmacology of DOV 102,677 is characterized. 2. This characterization was performed using radioligand binding and Neurotransmitter Uptake assays targeting the monoamine Neurotransmitter receptors. In addition, the effects of DOV 102,677 on extracellular Neurotransmitter levels were investigated using in vivo microdialysis. Finally, the effects of DOV 102,677 in the forced swim test, locomotor function, and response to prepulse inhibition was investigated.3. DOV 102,677 is a novel, "triple" Uptake inhibitor that suppresses [(3)H]dopamine (DA), [(3)H]norepinephrine (NE) and [(3)H]serotonin (5-HT) Uptake by recombinant human transporters with IC(50) values of 129, 103 and 133 nM, respectively. Radioligand binding to the dopamine (DAT), norepinephrine (NET), and serotonin (SERT) transporters is inhibited with k (i) values of 222, 1030, and 740 nM, respectively. DOV 102,677 (20 mg/kg IP) increased extracellular levels of DA and 5-HT in the prefrontal cortex to 320 and 280% above baseline 100 min after administration. DA levels were stably increased for the duration (240 min) of the study, but serotonin levels declined to baseline by 200 min after administration. NE levels increased linearly to a maximum of 348% at 240 min post-dosing. Consistent with these increases in NE levels, the density of beta-adrenoceptors was selectively decreased in the cortex of rats treated with DOV 102,677 (20 mg/kg per day, PO, 35 days). 4. DOV 102,677 dose-dependently reduced the amount of time spent immobile by rats in the forced swim test, a model predictive of antidepressant activity, with a minimum effective dose (MED) of 20 mg/kg and a maximal efficacy comparable to imipramine. This decrease in immobility time did not appear to result from increased motor activity. Further, DOV 102,677 was as effective as methylphenidate in reducing the amplitude of the startle response in juvenile mice, without notably altering motor activity. 5. In summary, DOV 102,677 is an orally active, "balanced" inhibitor of DAT, NET and SERT with therapeutic versatility in treating neuropsychiatric disorders beyond depression.
Piotr Popik - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological Profile of the “Triple” Monoamine Neurotransmitter Uptake Inhibitor, DOV 102,677
Cellular and Molecular Neurobiology, 2006Co-Authors: Piotr Popik, Martyna Krawczyk, Krystyna Golembiowska, Gabriel Nowak, Aaron Janowsky, Phil Skolnick, Arnold Lippa, Anthony S. BasileAbstract:1. The molecular and behavioral pharmacology of DOV 102,677 is characterized. 2. This characterization was performed using radioligand binding and Neurotransmitter Uptake assays targeting the monoamine Neurotransmitter receptors. In addition, the effects of DOV 102,677 on extracellular Neurotransmitter levels were investigated using in vivo microdialysis. Finally, the effects of DOV 102,677 in the forced swim test, locomotor function, and response to prepulse inhibition was investigated. 3. DOV 102,677 is a novel, “triple” Uptake inhibitor that suppresses [^3H]dopamine (DA), [^3H]norepinephrine (NE) and [^3H]serotonin (5-HT) Uptake by recombinant human transporters with IC_50 values of 129, 103 and 133 nM, respectively. Radioligand binding to the dopamine (DAT), norepinephrine (NET), and serotonin (SERT) transporters is inhibited with k _i values of 222, 1030, and 740 nM, respectively. DOV 102,677 (20 mg/kg IP) increased extracellular levels of DA and 5-HT in the prefrontal cortex to 320 and 280% above baseline 100 min after administration. DA levels were stably increased for the duration (240 min) of the study, but serotonin levels declined to baseline by 200 min after administration. NE levels increased linearly to a maximum of 348% at 240 min post-dosing. Consistent with these increases in NE levels, the density of β-adrenoceptors was selectively decreased in the cortex of rats treated with DOV 102,677 (20 mg/kg per day, PO, 35 days). 4. DOV 102,677 dose-dependently reduced the amount of time spent immobile by rats in the forced swim test, a model predictive of antidepressant activity, with a minimum effective dose (MED) of 20 mg/kg and a maximal efficacy comparable to imipramine. This decrease in immobility time did not appear to result from increased motor activity. Further, DOV 102,677 was as effective as methylphenidate in reducing the amplitude of the startle response in juvenile mice, without notably altering motor activity. 5. In summary, DOV 102,677 is an orally active, “balanced” inhibitor of DAT, NET and SERT with therapeutic versatility in treating neuropsychiatric disorders beyond depression.
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Pharmacological profile of the "triple" monoamine Neurotransmitter Uptake inhibitor, DOV 102,677.
Cellular and molecular neurobiology, 2006Co-Authors: Piotr Popik, Martyna Krawczyk, Krystyna Golembiowska, Gabriel Nowak, Aaron Janowsky, Phil Skolnick, Arnold Lippa, Anthony S. BasileAbstract:1. The molecular and behavioral pharmacology of DOV 102,677 is characterized. 2. This characterization was performed using radioligand binding and Neurotransmitter Uptake assays targeting the monoamine Neurotransmitter receptors. In addition, the effects of DOV 102,677 on extracellular Neurotransmitter levels were investigated using in vivo microdialysis. Finally, the effects of DOV 102,677 in the forced swim test, locomotor function, and response to prepulse inhibition was investigated.3. DOV 102,677 is a novel, "triple" Uptake inhibitor that suppresses [(3)H]dopamine (DA), [(3)H]norepinephrine (NE) and [(3)H]serotonin (5-HT) Uptake by recombinant human transporters with IC(50) values of 129, 103 and 133 nM, respectively. Radioligand binding to the dopamine (DAT), norepinephrine (NET), and serotonin (SERT) transporters is inhibited with k (i) values of 222, 1030, and 740 nM, respectively. DOV 102,677 (20 mg/kg IP) increased extracellular levels of DA and 5-HT in the prefrontal cortex to 320 and 280% above baseline 100 min after administration. DA levels were stably increased for the duration (240 min) of the study, but serotonin levels declined to baseline by 200 min after administration. NE levels increased linearly to a maximum of 348% at 240 min post-dosing. Consistent with these increases in NE levels, the density of beta-adrenoceptors was selectively decreased in the cortex of rats treated with DOV 102,677 (20 mg/kg per day, PO, 35 days). 4. DOV 102,677 dose-dependently reduced the amount of time spent immobile by rats in the forced swim test, a model predictive of antidepressant activity, with a minimum effective dose (MED) of 20 mg/kg and a maximal efficacy comparable to imipramine. This decrease in immobility time did not appear to result from increased motor activity. Further, DOV 102,677 was as effective as methylphenidate in reducing the amplitude of the startle response in juvenile mice, without notably altering motor activity. 5. In summary, DOV 102,677 is an orally active, "balanced" inhibitor of DAT, NET and SERT with therapeutic versatility in treating neuropsychiatric disorders beyond depression.
Martyna Krawczyk - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological Profile of the “Triple” Monoamine Neurotransmitter Uptake Inhibitor, DOV 102,677
Cellular and Molecular Neurobiology, 2006Co-Authors: Piotr Popik, Martyna Krawczyk, Krystyna Golembiowska, Gabriel Nowak, Aaron Janowsky, Phil Skolnick, Arnold Lippa, Anthony S. BasileAbstract:1. The molecular and behavioral pharmacology of DOV 102,677 is characterized. 2. This characterization was performed using radioligand binding and Neurotransmitter Uptake assays targeting the monoamine Neurotransmitter receptors. In addition, the effects of DOV 102,677 on extracellular Neurotransmitter levels were investigated using in vivo microdialysis. Finally, the effects of DOV 102,677 in the forced swim test, locomotor function, and response to prepulse inhibition was investigated. 3. DOV 102,677 is a novel, “triple” Uptake inhibitor that suppresses [^3H]dopamine (DA), [^3H]norepinephrine (NE) and [^3H]serotonin (5-HT) Uptake by recombinant human transporters with IC_50 values of 129, 103 and 133 nM, respectively. Radioligand binding to the dopamine (DAT), norepinephrine (NET), and serotonin (SERT) transporters is inhibited with k _i values of 222, 1030, and 740 nM, respectively. DOV 102,677 (20 mg/kg IP) increased extracellular levels of DA and 5-HT in the prefrontal cortex to 320 and 280% above baseline 100 min after administration. DA levels were stably increased for the duration (240 min) of the study, but serotonin levels declined to baseline by 200 min after administration. NE levels increased linearly to a maximum of 348% at 240 min post-dosing. Consistent with these increases in NE levels, the density of β-adrenoceptors was selectively decreased in the cortex of rats treated with DOV 102,677 (20 mg/kg per day, PO, 35 days). 4. DOV 102,677 dose-dependently reduced the amount of time spent immobile by rats in the forced swim test, a model predictive of antidepressant activity, with a minimum effective dose (MED) of 20 mg/kg and a maximal efficacy comparable to imipramine. This decrease in immobility time did not appear to result from increased motor activity. Further, DOV 102,677 was as effective as methylphenidate in reducing the amplitude of the startle response in juvenile mice, without notably altering motor activity. 5. In summary, DOV 102,677 is an orally active, “balanced” inhibitor of DAT, NET and SERT with therapeutic versatility in treating neuropsychiatric disorders beyond depression.
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Pharmacological profile of the "triple" monoamine Neurotransmitter Uptake inhibitor, DOV 102,677.
Cellular and molecular neurobiology, 2006Co-Authors: Piotr Popik, Martyna Krawczyk, Krystyna Golembiowska, Gabriel Nowak, Aaron Janowsky, Phil Skolnick, Arnold Lippa, Anthony S. BasileAbstract:1. The molecular and behavioral pharmacology of DOV 102,677 is characterized. 2. This characterization was performed using radioligand binding and Neurotransmitter Uptake assays targeting the monoamine Neurotransmitter receptors. In addition, the effects of DOV 102,677 on extracellular Neurotransmitter levels were investigated using in vivo microdialysis. Finally, the effects of DOV 102,677 in the forced swim test, locomotor function, and response to prepulse inhibition was investigated.3. DOV 102,677 is a novel, "triple" Uptake inhibitor that suppresses [(3)H]dopamine (DA), [(3)H]norepinephrine (NE) and [(3)H]serotonin (5-HT) Uptake by recombinant human transporters with IC(50) values of 129, 103 and 133 nM, respectively. Radioligand binding to the dopamine (DAT), norepinephrine (NET), and serotonin (SERT) transporters is inhibited with k (i) values of 222, 1030, and 740 nM, respectively. DOV 102,677 (20 mg/kg IP) increased extracellular levels of DA and 5-HT in the prefrontal cortex to 320 and 280% above baseline 100 min after administration. DA levels were stably increased for the duration (240 min) of the study, but serotonin levels declined to baseline by 200 min after administration. NE levels increased linearly to a maximum of 348% at 240 min post-dosing. Consistent with these increases in NE levels, the density of beta-adrenoceptors was selectively decreased in the cortex of rats treated with DOV 102,677 (20 mg/kg per day, PO, 35 days). 4. DOV 102,677 dose-dependently reduced the amount of time spent immobile by rats in the forced swim test, a model predictive of antidepressant activity, with a minimum effective dose (MED) of 20 mg/kg and a maximal efficacy comparable to imipramine. This decrease in immobility time did not appear to result from increased motor activity. Further, DOV 102,677 was as effective as methylphenidate in reducing the amplitude of the startle response in juvenile mice, without notably altering motor activity. 5. In summary, DOV 102,677 is an orally active, "balanced" inhibitor of DAT, NET and SERT with therapeutic versatility in treating neuropsychiatric disorders beyond depression.
Krystyna Golembiowska - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological Profile of the “Triple” Monoamine Neurotransmitter Uptake Inhibitor, DOV 102,677
Cellular and Molecular Neurobiology, 2006Co-Authors: Piotr Popik, Martyna Krawczyk, Krystyna Golembiowska, Gabriel Nowak, Aaron Janowsky, Phil Skolnick, Arnold Lippa, Anthony S. BasileAbstract:1. The molecular and behavioral pharmacology of DOV 102,677 is characterized. 2. This characterization was performed using radioligand binding and Neurotransmitter Uptake assays targeting the monoamine Neurotransmitter receptors. In addition, the effects of DOV 102,677 on extracellular Neurotransmitter levels were investigated using in vivo microdialysis. Finally, the effects of DOV 102,677 in the forced swim test, locomotor function, and response to prepulse inhibition was investigated. 3. DOV 102,677 is a novel, “triple” Uptake inhibitor that suppresses [^3H]dopamine (DA), [^3H]norepinephrine (NE) and [^3H]serotonin (5-HT) Uptake by recombinant human transporters with IC_50 values of 129, 103 and 133 nM, respectively. Radioligand binding to the dopamine (DAT), norepinephrine (NET), and serotonin (SERT) transporters is inhibited with k _i values of 222, 1030, and 740 nM, respectively. DOV 102,677 (20 mg/kg IP) increased extracellular levels of DA and 5-HT in the prefrontal cortex to 320 and 280% above baseline 100 min after administration. DA levels were stably increased for the duration (240 min) of the study, but serotonin levels declined to baseline by 200 min after administration. NE levels increased linearly to a maximum of 348% at 240 min post-dosing. Consistent with these increases in NE levels, the density of β-adrenoceptors was selectively decreased in the cortex of rats treated with DOV 102,677 (20 mg/kg per day, PO, 35 days). 4. DOV 102,677 dose-dependently reduced the amount of time spent immobile by rats in the forced swim test, a model predictive of antidepressant activity, with a minimum effective dose (MED) of 20 mg/kg and a maximal efficacy comparable to imipramine. This decrease in immobility time did not appear to result from increased motor activity. Further, DOV 102,677 was as effective as methylphenidate in reducing the amplitude of the startle response in juvenile mice, without notably altering motor activity. 5. In summary, DOV 102,677 is an orally active, “balanced” inhibitor of DAT, NET and SERT with therapeutic versatility in treating neuropsychiatric disorders beyond depression.
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Pharmacological profile of the "triple" monoamine Neurotransmitter Uptake inhibitor, DOV 102,677.
Cellular and molecular neurobiology, 2006Co-Authors: Piotr Popik, Martyna Krawczyk, Krystyna Golembiowska, Gabriel Nowak, Aaron Janowsky, Phil Skolnick, Arnold Lippa, Anthony S. BasileAbstract:1. The molecular and behavioral pharmacology of DOV 102,677 is characterized. 2. This characterization was performed using radioligand binding and Neurotransmitter Uptake assays targeting the monoamine Neurotransmitter receptors. In addition, the effects of DOV 102,677 on extracellular Neurotransmitter levels were investigated using in vivo microdialysis. Finally, the effects of DOV 102,677 in the forced swim test, locomotor function, and response to prepulse inhibition was investigated.3. DOV 102,677 is a novel, "triple" Uptake inhibitor that suppresses [(3)H]dopamine (DA), [(3)H]norepinephrine (NE) and [(3)H]serotonin (5-HT) Uptake by recombinant human transporters with IC(50) values of 129, 103 and 133 nM, respectively. Radioligand binding to the dopamine (DAT), norepinephrine (NET), and serotonin (SERT) transporters is inhibited with k (i) values of 222, 1030, and 740 nM, respectively. DOV 102,677 (20 mg/kg IP) increased extracellular levels of DA and 5-HT in the prefrontal cortex to 320 and 280% above baseline 100 min after administration. DA levels were stably increased for the duration (240 min) of the study, but serotonin levels declined to baseline by 200 min after administration. NE levels increased linearly to a maximum of 348% at 240 min post-dosing. Consistent with these increases in NE levels, the density of beta-adrenoceptors was selectively decreased in the cortex of rats treated with DOV 102,677 (20 mg/kg per day, PO, 35 days). 4. DOV 102,677 dose-dependently reduced the amount of time spent immobile by rats in the forced swim test, a model predictive of antidepressant activity, with a minimum effective dose (MED) of 20 mg/kg and a maximal efficacy comparable to imipramine. This decrease in immobility time did not appear to result from increased motor activity. Further, DOV 102,677 was as effective as methylphenidate in reducing the amplitude of the startle response in juvenile mice, without notably altering motor activity. 5. In summary, DOV 102,677 is an orally active, "balanced" inhibitor of DAT, NET and SERT with therapeutic versatility in treating neuropsychiatric disorders beyond depression.