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Paige Erin Mahaney - One of the best experts on this subject based on the ideXlab platform.
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structure activity relationships of the 1 amino 3 1h indol 1 yl 3 phenylpropan 2 ol series of Monoamine Reuptake Inhibitors
Bioorganic & Medicinal Chemistry Letters, 2009Co-Authors: Paige Erin Mahaney, Richard D Coghlan, Stephen Todd Cohn, Gavin David Heffernan, Christine Huselton, Eugene A Terefenko, An T Vu, Puwen Zhang, Kevin D Burroughs, Scott CosmiAbstract:Abstract The SAR of a series of 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols as Monoamine Reuptake Inhibitors, with a goal to improve both potency toward inhibiting the norepinephrine transporter and selectivity over the serotonin transporter, is reported. The effect of specific substitution on both the 3-phenyl group and the indole moiety were explored. This study led to the discovery of compound 20 which inhibited the norepinephrine transporter with an IC50 value of 4 nM while exhibiting 86-fold selectivity over the serotonin transporter.
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discovery of a new series of Monoamine Reuptake Inhibitors the 1 amino 3 1h indol 1 yl 3 phenylpropan 2 ols
Bioorganic & Medicinal Chemistry Letters, 2009Co-Authors: Paige Erin Mahaney, Oliver J Mcconnell, Yingru Zhang, Eric S Manas, Douglas M Ho, Darlene C Deecher, Eugene John TrybulskiAbstract:Abstract A novel series of Monoamine Reuptake Inhibitors, the 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols, have been discovered by combining virtual and focused screening efforts with design techniques. Synthesis of the two diastereomeric isomers of the molecule followed by chiral resolution of each enantiomer revealed the (2R,3S)-isomer to be a potent norepinephrine Reuptake inhibitor (IC50 = 28 nM) with excellent selectivity over the dopamine transporter and 13-fold selectivity over the serotonin transporter.
D J Heal - One of the best experts on this subject based on the ideXlab platform.
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comparison of the thermogenic and hypophagic effects of sibutramine s metabolite 2 and other Monoamine Reuptake Inhibitors
European Journal of Pharmacology, 2002Co-Authors: Ian P Connoley, D J Heal, Jonathan Harrison, M J StockAbstract:Abstract The thermogenic and hypophagic effects of sibutramine's metabolite (metabolite 2), a 5-hydroxytryptamine (5-HT) and noradrenaline Reuptake inhibitor, were investigated in rats and compared with duloxetine and bupropion. Metabolite 2 increased colonic temperature for 2.5–4.5 h. Duloxetine was also thermogenic but was less effective than metabolite 2. Bupropion similarly increased colonic temperature and was as efficacious, but less potent, than metabolite 2. At −8 °C, metabolite 2, duloxetine and bupropion all decreased response to heat reinforcement and reduced colonic temperature. Metabolite 2 produced a sustained increase in oxygen consumption (VO 2 ) at 29 °C from 90 to 240 min, whereas duloxetine was far less effective. Bupropion rapidly enhanced VO 2 , but its effect was less prolonged than that of metabolite 2. Metabolite 2 markedly reduced 24-h food intake. Duloxetine decreased feeding although its effect was shorter-lived, but bupropion was without effect. Thus, sibutramine's antiobesity action is probably attributable to effects on energy intake and expenditure. Duloxetine shares these properties, but is generally less efficacious. Any potential weight-reducing effect of bupropion is probably due to thermogenesis.
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in vivo criteria to differentiate Monoamine Reuptake Inhibitors from releasing agents sibutramine is a Reuptake inhibitor
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: C Gundlah, K F Martin, D J Heal, Sidney B AuerbachAbstract:Because Monoamine Reuptake Inhibitors and releasing agents both increase extracellular neurotransmitter levels, establishing in vivo experimental criteria for their classification has been difficult. Using microdialysis in the hypothalamus of unanesthetized rats, we provide evidence that serotonin- (5-HT) selective and nonselective Reuptake Inhibitors can be distinguished from the 5-HT-releasing agent fenfluramine by four criteria: 1) Systemic fenfluramine produces a much greater increase in 5-HT than the Reuptake Inhibitors. 2) The 5-HT somatodendritic autoreceptor agonist, (±)-8-hydroxy-(dipropylamino)tetralin (8-OH-DPAT), attenuates the increase in 5-HT produced by Reuptake Inhibitors, but not by fenfluramine. 3) The large increase in 5-HT produced by infusion of Reuptake Inhibitors into the hypothalamus is attenuated by their systemic administration. However, systemic injection of fenfluramine during its local infusion does not attenuate this increase. 4) Reuptake inhibitor pretreatment attenuates fenfluramine-induced increases in 5-HT. According to these criteria, the in vivo effects of the novel antiobesity drug sibutramine are consistent with its characterization as a 5-HT Reuptake inhibitor and not a 5-HT releaser. Thus, sibutramine produced increases in hypothalamic 5-HT similar in magnitude to the effects of the known Reuptake Inhibitors, and the increase was attenuated by 8-OH-DPAT. Also, sibutramine attenuated fenfluramine-induced 5-HT release. Systemic administration of sibutramine failed to attenuate the increase in 5-HT produced by its local infusion, suggesting that this criterion is not applicable to compounds with low affinity for the 5-HT transporter.
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comparison of the effects of sibutramine and other Monoamine Reuptake Inhibitors on food intake in the rat
British Journal of Pharmacology, 1997Co-Authors: Helen C Jackson, Andrew M Needham, Lisa J Hutchins, Sarah E Mazurkiewicz, D J HealAbstract:1 The effects of the potent 5-hydroxytryptamine (5-HT) and noradrenaline Reuptake inhibitor (serotonin-noradrenaline Reuptake inhibitor, SNRI), sibutramine, on the cumulative food intake of freely-feeding male Sprague-Dawley rats during an 8 h dark period were investigated and compared to those of the selective 5-HT Reuptake inhibitor (selective serotonin Reuptake inhibitor, SSRI), fluoxetine; the selective noradrenaline Reuptake inhibitor, nisoxetine; the 5-HT and noradrenaline Reuptake Inhibitors, venlafaxine and duloxetine; and the 5-HT releaser and 5-HT Reuptake inhibitor, (+)-fenfluramine. 2 Sibutramine (3 and 10 mg kg−1, p.o.) and (+)-fenfluramine (1 and 3 mg kg−1, p.o.) produced a significant, dose-dependent decrease in food intake over the 8 h dark period. These responses became apparent within the first 2 h following drug administration. 3 Fluoxetine (3, 10 and 30 mg kg−1, p.o.), and nisoxetine (3, 10 and 30 mg kg−1, p.o.) had no significant effect on food intake during the 8 h dark period. However, a combination of fluoxetine and nisoxetine (30 mg kg−1, p.o., of each) significantly decreased food intake 2 and 8 h after drug administration. 4 Venlafaxine (100 and 300 mg kg−1, p.o.) and duloxetine (30 mg kg−1, p.o.) also significantly decreased food intake in the 2 and 8 h following drug administration. 5 The results of this study demonstrate that inhibition of 5-HT and noradrenaline Reuptake by sibutramine, venlafaxine, duloxetine, or by a combination of fluoxetine and nisoxetine, markedly reduces food intake in freely-feeding rats and suggest that this may be a novel approach for the treatment of obesity. British Journal of Pharmacology (1997) 121, 1758–1762; doi:10.1038/sj.bjp.0701312
Scott Cosmi - One of the best experts on this subject based on the ideXlab platform.
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structure activity relationships of the 1 amino 3 1h indol 1 yl 3 phenylpropan 2 ol series of Monoamine Reuptake Inhibitors
Bioorganic & Medicinal Chemistry Letters, 2009Co-Authors: Paige Erin Mahaney, Richard D Coghlan, Stephen Todd Cohn, Gavin David Heffernan, Christine Huselton, Eugene A Terefenko, An T Vu, Puwen Zhang, Kevin D Burroughs, Scott CosmiAbstract:Abstract The SAR of a series of 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols as Monoamine Reuptake Inhibitors, with a goal to improve both potency toward inhibiting the norepinephrine transporter and selectivity over the serotonin transporter, is reported. The effect of specific substitution on both the 3-phenyl group and the indole moiety were explored. This study led to the discovery of compound 20 which inhibited the norepinephrine transporter with an IC50 value of 4 nM while exhibiting 86-fold selectivity over the serotonin transporter.
Eugene John Trybulski - One of the best experts on this subject based on the ideXlab platform.
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discovery of a new series of Monoamine Reuptake Inhibitors the 1 amino 3 1h indol 1 yl 3 phenylpropan 2 ols
Bioorganic & Medicinal Chemistry Letters, 2009Co-Authors: Paige Erin Mahaney, Oliver J Mcconnell, Yingru Zhang, Eric S Manas, Douglas M Ho, Darlene C Deecher, Eugene John TrybulskiAbstract:Abstract A novel series of Monoamine Reuptake Inhibitors, the 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols, have been discovered by combining virtual and focused screening efforts with design techniques. Synthesis of the two diastereomeric isomers of the molecule followed by chiral resolution of each enantiomer revealed the (2R,3S)-isomer to be a potent norepinephrine Reuptake inhibitor (IC50 = 28 nM) with excellent selectivity over the dopamine transporter and 13-fold selectivity over the serotonin transporter.
Aloke K. Dutta - One of the best experts on this subject based on the ideXlab platform.
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structural exploration of 3s 6s 6 benzhydryl n benzyltetrahydro 2h pyran 3 amine analogues identification of potent triple Monoamine Reuptake Inhibitors as potential antidepressants
ChemMedChem, 2012Co-Authors: Soumava Santra, Bhaskar Gopishetty, Sanjib Gogoi, Tamara Antonio, Juan Zhen, Maarten E A Reith, Aloke K. DuttaAbstract:Unipolar depression is ranked as number one before all other somatic and psychiatric illnesses. In spite of its prevalence, the underlying causes of depression are still unclear [1]. This disorder is a significant health problem and 10-20% of all adults suffer from this disease[1]. Different classes of antidepressants have been developed over the past decades. Antidepressants are traditionally thought to elicit their therapeutic effects by increasing extraneuronal concentrations of serotonin and norepinephrine [2]. Earlier tricyclic antidepressants displayed variable norepinephrine and serotonin uptake inhibitory activity, while exhibiting considerable side effects in addition to antidepressant effects due to non-specific interactions in the central nervous system (CNS) [3] Subsequent development of selective serotonin Reuptake Inhibitors (SSRIs) and serotonin/norepinephrine Reuptake Inhibitors (SNRIs) are second generation antidepressants which provided drugs with much more selective interaction at serotonin and norepinephrine systems [4-7]. By virtue of their interaction with the SERT and NET only, these drugs had appreciable less unwanted side effects than tricyclic antidepressants [8-9]. An SNRI such as Venlafaxine exhibits antidepressant activity in clinical trials and displays somewhat greater response and remission rates compared to SSRIs [10]. However, a significant unmet need for more improved therapy still exists, as large numbers of depressed people are still refractory to the current existing therapies. In addition, a significant number of people suffer from relapse after treatment with current therapies [11].
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An improved asymmetric synthetic route to a novel triple uptake inhibitor antidepressant (2S,4R,5R)-2-benzhydryl-5-((4-methoxybenzyl)amino)tetrahydro-2H-pyran-4-ol (D-142).
Tetrahedron-asymmetry, 2011Co-Authors: Bhaskar Gopishetty, Sanjib Gogoi, Aloke K. DuttaAbstract:Abstract Triple Monoamine Reuptake Inhibitors have been implicated in the development of a new generation of antidepressants with higher efficacy than the currently existing therapies. In this paper, we have developed an alternative efficient synthetic route for triple Monoamine Reuptake inhibitor D-142 in 18.5% overall yield in 11 steps starting from diphenylmethane. D-142 was developed by us recently. The key step of the present synthetic strategy is the preferential formation of a bromohydrin from olefin via a cis -bromonium intermediate, which introduced significant efficiency in the overall synthesis. Furthermore, we have developed an efficient way to recycle the optically active intermediate diol back to the desired chiral epoxide.