The Experts below are selected from a list of 9243 Experts worldwide ranked by ideXlab platform
Feng Zhu - One of the best experts on this subject based on the ideXlab platform.
-
what contributes to serotonin Norepinephrine Reuptake Inhibitors dual targeting mechanism the key role of transmembrane domain 6 in human serotonin and Norepinephrine transporters revealed by molecular dynamics simulation
ACS Chemical Neuroscience, 2018Co-Authors: Weiwei Xue, Guoxun Zheng, Panpan Wang, Fengyuan Yang, Xiaojun Yao, Yu Zong Chen, Feng ZhuAbstract:Dual inhibition of serotonin and Norepinephrine transporters (hSERT and hNET) gives greatly improved efficacy and tolerability for treating major depressive disorder (MDD) compared with selective Reuptake Inhibitors. Pioneer studies provided valuable information on structure, function, and pharmacology of drugs targeting both hSERT and hNET (serotonin–Norepinephrine Reuptake Inhibitors, SNRIs), and the differential binding mechanism between SNRIs and selective Inhibitors of 5-HT (SSRIs) or NE (sNRIs) to their corresponding targets was expected to be able to facilitate the discovery of a privileged drug-like scaffold with improved efficacy. However, the dual-target mechanism of SNRIs was still elusive, and the binding mode distinguishing SNRIs from SSRIs and sNRIs was also unclear. Herein, an integrated computational strategy was adopted to discover the binding mode shared by all FDA approved SNRIs. The comparative analysis of binding free energy at the per-residue level discovered that residues Phe335, Le...
-
What Contributes to Serotonin–Norepinephrine Reuptake Inhibitors’ Dual-Targeting Mechanism? The Key Role of Transmembrane Domain 6 in Human Serotonin and Norepinephrine Transporters Revealed by Molecular Dynamics Simulation
2018Co-Authors: Weiwei Xue, Guoxun Zheng, Panpan Wang, Fengyuan Yang, Xiaojun Yao, Yu Zong Chen, Feng ZhuAbstract:Dual inhibition of serotonin and Norepinephrine transporters (hSERT and hNET) gives greatly improved efficacy and tolerability for treating major depressive disorder (MDD) compared with selective Reuptake Inhibitors. Pioneer studies provided valuable information on structure, function, and pharmacology of drugs targeting both hSERT and hNET (serotonin–Norepinephrine Reuptake Inhibitors, SNRIs), and the differential binding mechanism between SNRIs and selective Inhibitors of 5-HT (SSRIs) or NE (sNRIs) to their corresponding targets was expected to be able to facilitate the discovery of a privileged drug-like scaffold with improved efficacy. However, the dual-target mechanism of SNRIs was still elusive, and the binding mode distinguishing SNRIs from SSRIs and sNRIs was also unclear. Herein, an integrated computational strategy was adopted to discover the binding mode shared by all FDA approved SNRIs. The comparative analysis of binding free energy at the per-residue level discovered that residues Phe335, Leu337, Gly338, and Val343 located at the transmembrane domain 6 (TM6) of hSERT (the corresponding residues Phe317, Leu319, Gly320, and Val325 in hNET) were the determinants accounting for SNRIs’ dual-acting inhibition, while residues lining TM3 and 8 (Ile172, Ser438, Thr439, and Leu443 in hSERT; Val148, Ser419, Ser420, and Met424 in hNET) contributed less to the binding of SNRIs than that of SSRIs and sNRIs. Based on these results, the distances between an SNRI’s centroid and the centroids of its two aromatic rings (measuring the depth of rings stretching into hydrophobic pockets) were discovered as the key to the SNRIs’ dual-targeting mechanism. This finding revealed SNRIs’ binding mechanism at an atomistic level, which could be further utilized as structural blueprints for the rational design of privileged drug-like scaffolds treating MDD
-
Exploring the Inhibitory Mechanism of Approved Selective Norepinephrine Reuptake Inhibitors and Reboxetine Enantiomers by Molecular Dynamics Study
Scientific reports, 2016Co-Authors: Guoxun Zheng, Weiwei Xue, Panpan Wang, Fengyuan Yang, Xiaojun Yao, Feng ZhuAbstract:Selective Norepinephrine Reuptake Inhibitors (sNRIs) provide an effective class of approved antipsychotics, whose inhibitory mechanism could facilitate the discovery of privileged scaffolds with enhanced drug efficacy. However, the crystal structure of human Norepinephrine transporter (hNET) has not been determined yet and the inhibitory mechanism of sNRIs remains elusive. In this work, multiple computational methods were integrated to explore the inhibitory mechanism of approved sNRIs (atomoxetine, maprotiline, reboxetine and viloxazine), and 3 lines of evidences were provided to verify the calculation results. Consequently, a binding mode defined by interactions between three chemical moieties in sNRIs and eleven residues in hNET was identified as shared by approved sNRIs. In the meantime, binding modes of reboxetine's enantiomers with hNET were compared. 6 key residues favoring the binding of (S, S)-reboxetine over that of (R, R)-reboxetine were discovered. This is the first study reporting that those 11 residues are the common determinants for the binding of approved sNRIs. The identified binding mode shed light on the inhibitory mechanism of approved sNRIs, which could help identify novel scaffolds with improved drug efficacy.
Puwen Zhang - One of the best experts on this subject based on the ideXlab platform.
-
1-(Indolin-1-yl)-1-phenyl-3-propan-2-olamines as potent and selective Norepinephrine Reuptake Inhibitors.
Journal of medicinal chemistry, 2010Co-Authors: Stephen Todd Cohn, Paige Erin Mahaney, Puwen Zhang, Jenifer A. Bray, Elizabeth Koury, Grace H. Johnston, Kim Callain Younghee, Scott Cosmi, Darlene C. DeecherAbstract:Efforts to identify new selective and potent Norepinephrine Reuptake Inhibitors (NRIs) for multiple indications by structural modification of the previous 3-(arylamino)-3-phenylpropan-2-olamine scaffold led to the discovery of a novel series of 1-(indolin-1-yl)-1-phenyl-3-propan-2-olamines (9). Investigation of the structure−activity relationships revealed that small alkyl substitution at the C3 position of the indoline ring enhanced selectivity for the Norepinephrine transporter (NET) over the serotonin transporter (SERT). Several compounds bearing a 3,3-dimethyl group on the indoline ring, 9k, 9o,p, and 9s,t, exhibited potent inhibition of NET (IC50 = 2.7−6.5 nM) and excellent selectivity over both serotonin and dopamine transporters. The best example from this series, 9p, a potent and highly selective NRI, displayed oral efficacy in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction, a mouse p-phenylquinone (PPQ) model of acute visceral pain, and a rat spinal nerve ligation (...
-
Structure-activity relationships of Norepinephrine Reuptake Inhibitors with benzothiadiazine dioxide or dihydrosulfostyril cores.
Bioorganic & medicinal chemistry letters, 2010Co-Authors: Andrew Fensome, Casey C. Mccomas, Joel Adam Goldberg, Eugene John Trybulski, Richard Page Woodworth, Darlene C. Deecher, Garth T. Whiteside, Puwen ZhangAbstract:Abstract Two related series of selective Norepinephrine Reuptake Inhibitors were synthesized based on 3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide or 3,4-dihydrosulfostyril cores, and screened for monoamine Reuptake inhibition. Structure–activity relationships were determined for the series’ in vitro potency and selectivity versus serotonin or dopamine transporter inhibition, and analogs based on both cores were identified as potent and selective NRIs. The 3,4-dihydrosulfostyril series was further tested for microsome stability, and compound 16j, which was optimized for both potency and stability, showed efficacy in an in vivo model of thermoregulatory dysfunction.
-
1 or 3 3 amino 2 hydroxy 1 phenyl propyl 1 3 dihydro 2h benzimidazol 2 ones potent selective and orally efficacious Norepinephrine Reuptake Inhibitors
Journal of Medicinal Chemistry, 2009Co-Authors: Puwen Zhang, Andrew Fensome, Darlene C. Deecher, Elizabeth Koury, Eugene Anthony Terefenko, Jenifer Bray, James Harrison, Callain Younghee Kim, Lilly Mark, Casey Cameron MccomasAbstract:Sequential structural modifications of the aryloxypropanamine template (e.g., atomoxetine, 2) led to a novel series of 1-(3-amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective Norepinephrine Reuptake Inhibitors (NRIs). In general, this series of compounds potently blocked the human Norepinephrine transporter (hNET) while exhibiting selectivity at hNET against both the human serotonin (hSERT) and dopamine transporters (hDAT). Numerous compounds (e.g., 19−22) had low nonamolar hNET potency with IC50 values of 7−10 nM and excellent selectivity (>500 fold) at hNET over hSERT and hDAT. Several compounds, such as 20 and 22, were tested in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction and were efficacious at oral doses of 3 mg/kg in reducing the tail skin temperature. In addition, compound 20 was also studied in the rat hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain, respectively, and was orally efficacious at doses of 3...
-
Synthesis and activity of novel 1- or 3-(3-amino-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective Norepinephrine Reuptake Inhibitors.
Bioorganic & medicinal chemistry letters, 2008Co-Authors: Puwen Zhang, Paige Erin Mahaney, Eugene John Trybulski, Jenifer A. Bray, Terefenko Eugene Anthony, Casey Cameron Mccomas, Elizabeth Koury, Grace H. Johnston, Darlene C. DeecherAbstract:A series of novel 1- or 3-(3-amino-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective Norepinephrine Reuptake Inhibitors was discovered. Several compounds such as 15 and 20 showed good hNET potency. Compounds 15 and 20 also displayed excellent selectivity at hNET that appeared superior to those of reboxetine and atomoxetine (4 and 5).
-
Synthesis and activity of a new class of dual acting Norepinephrine and serotonin Reuptake Inhibitors: 3-(1H-indol-1-yl)-3-arylpropan-1-amines
Bioorganic & Medicinal Chemistry, 2006Co-Authors: Paige Erin Mahaney, An T Vu, Casey C. Mccomas, Lisa M. Nogle, William L. Watts, Ani Sarkahian, Nicole R. Sullivan, Puwen Zhang, Liza Leventhal, Albert J. UvegesAbstract:Compounds with a combination of Norepinephrine and serotonin Reuptake inhibition have been approved in the US and Europe for a number of indications, including major depressive disorder and pain disorders such as diabetic neuropathy and fibromyalgia. Efforts to design selective Norepinephrine Reuptake Inhibitors based on SAR from the aryloxypropanamine series of monoamine Reuptake Inhibitors have led to the identification of a potent new class of dual acting Norepinephrine and serotonin Reuptake Inhibitors, namely the 3-(1H-indol-1-yl)-3-arylpropan-1-amines.
Sarah Hudson - One of the best experts on this subject based on the ideXlab platform.
-
Synthesis and structure-activity relationships of selective Norepinephrine Reuptake Inhibitors (sNRI) with improved pharmaceutical characteristics.
Bioorganic & medicinal chemistry letters, 2008Co-Authors: Joseph Pontillo, Sarah Hudson, Marc J. Genicot, Beth A. Fleck, Kathleen Gogas, Brett Ching, Yinghong Gao, Todd Ewing, Anna AparicioAbstract:Abstract The design synthesis and SAR of a series of chiral ring-constrained Norepinephrine Reuptake Inhibitors with improved physicochemical properties is described. Typical compounds are potent (IC50s 1 μM) and stable to oxidation by human liver microsomes. In addition, the compounds exhibit a favorable polarity profile.
-
synthesis and structure activity relationships of selective Norepinephrine Reuptake Inhibitors snri with a heterocyclic ring constraint
Bioorganic & Medicinal Chemistry Letters, 2008Co-Authors: Sarah Hudson, Mehrak Kiankarimi, Wendy Eccles, Yalda S. Mostofi, Marc J. Genicot, Wesley J. Dwight, Beth A. Fleck, Kathleen Gogas, Warren WadeAbstract:The design, synthesis and SAR of a series of heterocyclic ring-constrained Norepinephrine Reuptake Inhibitors are described. As racemates, the best compounds compare favorably with atomoxetine (IC 50 ’s < 10 nM) in potency at the transporter.
-
Synthesis and structure-activity relationships of selective Norepinephrine Reuptake Inhibitors (sNRI) with a heterocyclic ring constraint.
Bioorganic & medicinal chemistry letters, 2008Co-Authors: Sarah Hudson, Mehrak Kiankarimi, Wendy Eccles, Yalda S. Mostofi, Marc J. Genicot, Wesley J. Dwight, Beth A. Fleck, Kathleen Gogas, Warren WadeAbstract:The design, synthesis and SAR of a series of heterocyclic ring-constrained Norepinephrine Reuptake Inhibitors are described. As racemates, the best compounds compare favorably with atomoxetine (IC 50 ’s
-
Structure-activity relationships of chiral selective Norepinephrine Reuptake Inhibitors (sNRI) with increased oxidative stability.
Bioorganic & medicinal chemistry letters, 2008Co-Authors: Sarah Hudson, Mehrak Kiankarimi, Wendy Eccles, Yalda S. Mostofi, Marc J. Genicot, Wesley J. Dwight, Beth A. Fleck, Kathleen Gogas, Anna Aparicio, Hua WangAbstract:Abstract The synthesis and SAR of a series of chiral heterocyclic ring-constrained Norepinephrine Reuptake Inhibitors are described. The best compounds compare favorably with atomoxetine in potency (IC50s 1 μM). In addition, the compounds are generally more stable than atomoxetine to oxidative metabolism and thus are likely to have lower clearance in humans.
-
Discovery of a potent, selective, and less flexible selective Norepinephrine Reuptake inhibitor (sNRI).
Bioorganic & medicinal chemistry letters, 2008Co-Authors: Joseph Pontillo, Sarah Hudson, Beth A. Fleck, Kathleen Gogas, Brett Ching, Yinghong Gao, Warren WadeAbstract:Abstract The design, synthesis, and SAR of a series of ring-constrained Norepinephrine Reuptake Inhibitors are described. A substantially rigid inhibitor with potent functional activity at the transporter (IC 50 = 8 nM) was used to develop a model for the distance and orientation of key features necessary for interaction with the Norepinephrine transporter (NET).
Paige Erin Mahaney - One of the best experts on this subject based on the ideXlab platform.
-
heterocyclic cycloalkanol ethylamines as Norepinephrine Reuptake Inhibitors
ChemInform, 2010Co-Authors: Joseph Peter Sabatucci, Paige Erin Mahaney, Darlene C. Deecher, Grace H. Johnston, Scott Cosmi, Jennifer Leiter, Kevin D. Burroughs, Yingru Zhang, Eugene John TrybulskiAbstract:A variety of heterocyclic cycloalkanol ethylamines are synthesized and evaluated as norephedrine Reuptake Inhibitors.
-
Heterocyclic cycloalkanol ethylamines as Norepinephrine Reuptake Inhibitors.
Bioorganic & medicinal chemistry letters, 2010Co-Authors: Joseph Peter Sabatucci, Paige Erin Mahaney, Darlene C. Deecher, Grace H. Johnston, Scott Cosmi, Jennifer Leiter, Kevin D. Burroughs, Yingru Zhang, Eugene John TrybulskiAbstract:A series of heterocyclic cycloalkanol ethylamines have been prepared to expand our Norepinephrine Reuptake inhibitor (NRI) program. Synthesis of a variety of heterocycles identified (+)-S-21, a potent NRI efficacious in an animal model for thermoregulatory dysfunction.
-
1-(Indolin-1-yl)-1-phenyl-3-propan-2-olamines as potent and selective Norepinephrine Reuptake Inhibitors.
Journal of medicinal chemistry, 2010Co-Authors: Stephen Todd Cohn, Paige Erin Mahaney, Puwen Zhang, Jenifer A. Bray, Elizabeth Koury, Grace H. Johnston, Kim Callain Younghee, Scott Cosmi, Darlene C. DeecherAbstract:Efforts to identify new selective and potent Norepinephrine Reuptake Inhibitors (NRIs) for multiple indications by structural modification of the previous 3-(arylamino)-3-phenylpropan-2-olamine scaffold led to the discovery of a novel series of 1-(indolin-1-yl)-1-phenyl-3-propan-2-olamines (9). Investigation of the structure−activity relationships revealed that small alkyl substitution at the C3 position of the indoline ring enhanced selectivity for the Norepinephrine transporter (NET) over the serotonin transporter (SERT). Several compounds bearing a 3,3-dimethyl group on the indoline ring, 9k, 9o,p, and 9s,t, exhibited potent inhibition of NET (IC50 = 2.7−6.5 nM) and excellent selectivity over both serotonin and dopamine transporters. The best example from this series, 9p, a potent and highly selective NRI, displayed oral efficacy in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction, a mouse p-phenylquinone (PPQ) model of acute visceral pain, and a rat spinal nerve ligation (...
-
Dual acting Norepinephrine Reuptake Inhibitors and 5-HT2A receptor antagonists: Identification, synthesis and activity of novel 4-aminoethyl-3-(phenylsulfonyl)-1H-indoles
Bioorganic & medicinal chemistry, 2009Co-Authors: Gavin David Heffernan, Paige Erin Mahaney, Richard D. Coghlan, Eric S. Manas, Mcdevitt Robert Emmett, Li Yanfang, Albert J. Robichaud, Christine Huselton, Peter D. Alfinito, Jenifer A. BrayAbstract:Abstract The discovery of a series of 4-aminoethyl-3-(phenylsulfonyl)-1H-indoles, dual acting Norepinephrine Reuptake Inhibitors (NRIs) and 5-HT2A receptor antagonists, is described. The synthesis and structure–activity relationship (SAR) of this novel series of compounds is also presented.
-
Synthesis and activity of novel 1- or 3-(3-amino-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective Norepinephrine Reuptake Inhibitors.
Bioorganic & medicinal chemistry letters, 2008Co-Authors: Puwen Zhang, Paige Erin Mahaney, Eugene John Trybulski, Jenifer A. Bray, Terefenko Eugene Anthony, Casey Cameron Mccomas, Elizabeth Koury, Grace H. Johnston, Darlene C. DeecherAbstract:A series of novel 1- or 3-(3-amino-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective Norepinephrine Reuptake Inhibitors was discovered. Several compounds such as 15 and 20 showed good hNET potency. Compounds 15 and 20 also displayed excellent selectivity at hNET that appeared superior to those of reboxetine and atomoxetine (4 and 5).
Yumeng Cao - One of the best experts on this subject based on the ideXlab platform.
-
Serotonin–Norepinephrine Reuptake Inhibitors for the prevention of migraine and vestibular migraine: a systematic review and meta-analysis
Regional anesthesia and pain medicine, 2020Co-Authors: Fengzhi Wang, Jiaoqi Wang, Yumeng CaoAbstract:Background and objectives The role of serotonin–Norepinephrine Reuptake Inhibitors (SNRIs) in migraine prophylaxis has not been completely established. Current treatments for vestibular migraine (VM) are based on scarce evidence. We aimed to perform an updated review focusing on the efficacy and tolerability of SNRIs for migraine and VM prevention. Methods We searched the PubMed, Web of Science, and Cochrane Library databases for relevant studies. The primary outcome was migraine frequency. In the case of VM, the Dizziness Handicap Inventory (DHI) scores and Vertigo Severity Scores (VSSs) were extracted. Results Six randomized controlled trials involving 418 patients were analyzed. Patients receiving SNRIs had fewer migraine days than those receiving a placebo (standardized mean difference −0.38, 95% CI −0.76 to −0.01, p=0.04). The effects of SNRIs and other active drugs were comparable. In patients with VM, venlafaxine had a significant advantage over other active drugs in decreasing the VSS (weighted mean difference (MD) −1.45, 95% CI −2.11 to −0.78, p Conclusions SNRIs were clinically safe and effective for migraine and VM prophylaxis, were better than a placebo, and not inferior to other active drugs. SNRIs may be a preferable choice for patients with VM with psychiatric disorders.
-
serotonin Norepinephrine Reuptake Inhibitors for the prevention of migraine and vestibular migraine a systematic review and meta analysis
Regional Anesthesia and Pain Medicine, 2020Co-Authors: Fengzhi Wang, Jiaoqi Wang, Yumeng CaoAbstract:Background and objectives The role of serotonin–Norepinephrine Reuptake Inhibitors (SNRIs) in migraine prophylaxis has not been completely established. Current treatments for vestibular migraine (VM) are based on scarce evidence. We aimed to perform an updated review focusing on the efficacy and tolerability of SNRIs for migraine and VM prevention. Methods We searched the PubMed, Web of Science, and Cochrane Library databases for relevant studies. The primary outcome was migraine frequency. In the case of VM, the Dizziness Handicap Inventory (DHI) scores and Vertigo Severity Scores (VSSs) were extracted. Results Six randomized controlled trials involving 418 patients were analyzed. Patients receiving SNRIs had fewer migraine days than those receiving a placebo (standardized mean difference −0.38, 95% CI −0.76 to −0.01, p=0.04). The effects of SNRIs and other active drugs were comparable. In patients with VM, venlafaxine had a significant advantage over other active drugs in decreasing the VSS (weighted mean difference (MD) −1.45, 95% CI −2.11 to −0.78, p Conclusions SNRIs were clinically safe and effective for migraine and VM prophylaxis, were better than a placebo, and not inferior to other active drugs. SNRIs may be a preferable choice for patients with VM with psychiatric disorders.
