Development of New Benzylpiperazine Derivatives as σ(1) Receptor Ligands with in Vivo Antinociceptive and Anti-Allodynic Effects.
Development of New Benzylpiperazine Derivatives as σ(1) Receptor Ligands with in Vivo Antinociceptive and Anti-Allodynic Effects.
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DOI：
10.1021/acschemneuro.1c00106
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发表时间：
2021-06-02
影响因子：
5
通讯作者：
Intagliata S
中科院分区：
文献类型：
--
作者：
Romeo G;Bonanno F;Wilson LL;Arena E;Modica MN;Pittalà V;Salerno L;Prezzavento O;McLaughlin JP;Intagliata S
σ-1 受体 (σ1R) 调节伤害性信号传导，推动寻找选择性拮抗剂，以利用这一有希望的靶标来治疗疼痛。在这项研究中，设计、合成了一系列新的苄基哌嗪基衍生物，并对其对 σ1R 的亲和力和对 σ-2 受体 (σ2R) 的选择性进行了表征。值得注意的是，3-环己基-1-{4-[(4-甲氧基苯基)甲基]哌嗪-1-基}丙-1-酮 (15) 在该系列中表现出最高的 σ1R 受体亲和力 (Ki σ1 = 1.6 nM)，与先导化合物 8 (Ki σ2/Ki σ1= 432）。化合物 15 在炎症性疼痛和神经性疼痛的慢性神经收缩损伤 (CCI) 的小鼠福尔马林测定中进行了进一步测试，其中它产生剂量依赖性（3-60 mg/kg，腹腔注射）的镇痛和抗异常疼痛作用。此外，化合物 15 在旋转试验中没有表现出显着效果，表明这种 σ1R 拮抗剂不会产生镇静作用或损害运动反应。总体而言，这些结果鼓励进一步开发基于苄基哌嗪的 σ1R 拮抗剂作为慢性疼痛的潜在疗法。
σ-1 receptors (σ1R) modulate nociceptive signaling, driving the search for selective antagonists to take advantage of this promising target to treat pain. In this study, a new series of benzylpiperazinyl derivatives has been designed, synthesized, and characterized for their affinities toward σ1R and selectivity over the σ-2 receptor (σ2R). Notably, 3-cyclohexyl-1-{4-[(4-methoxyphenyl)methyl]piperazin-1-yl}propan-1-one (15) showed the highest σ1R receptor affinity (Ki σ1 = 1.6 nM) among the series with a significant improvement of the σ1R selectivity (Ki σ2/Ki σ1= 886) compared to the lead compound 8 (Ki σ2/Ki σ1= 432). Compound 15 was further tested in a mouse formalin assay of inflammatory pain and chronic nerve constriction injury (CCI) of neuropathic pain, where it produced dose-dependent (3–60 mg/kg, i.p.) antinociception and anti-allodynic effects. Moreover, compound 15 demonstrated no significant effects in a rotarod assay, suggesting that this σ1R antagonist did not produce sedation or impair locomotor responses. Overall, these results encourage the further development of our benzylpiperazine-based σ1R antagonists as potential therapeutics for chronic pain.
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影响因子：
11.1
作者：
Chu UB;Mavlyutov TA;Chu ML;Yang H;Schulman A;Mesangeau C;McCurdy CR;Guo LW;Ruoho AE
通讯作者：
Ruoho AE
DOI：
10.1126/science.abe9403
发表时间：
2020-12-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gordon DE;Hiatt J;Bouhaddou M;Rezelj VV;Ulferts S;Braberg H;Jureka AS;Obernier K;Guo JZ;Batra J;Kaake RM;Weckstein AR;Owens TW;Gupta M;Pourmal S;Titus EW;Cakir M;Soucheray M;McGregor M;Cakir Z;Jang G;O'Meara MJ;Tummino TA;Zhang Z;Foussard H;Rojc A;Zhou Y;Kuchenov D;Hüttenhain R;Xu J;Eckhardt M;Swaney DL;Fabius JM;Ummadi M;Tutuncuoglu B;Rathore U;Modak M;Haas P;Haas KM;Naing ZZC;Pulido EH;Shi Y;Barrio-Hernandez I;Memon D;Petsalaki E;Dunham A;Marrero MC;Burke D;Koh C;Vallet T;Silvas JA;Azumaya CM;Billesbølle C;Brilot AF;Campbell MG;Diallo A;Dickinson MS;Diwanji D;Herrera N;Hoppe N;Kratochvil HT;Liu Y;Merz GE;Moritz M;Nguyen HC;Nowotny C;Puchades C;Rizo AN;Schulze-Gahmen U;Smith AM;Sun M;Young ID;Zhao J;Asarnow D;Biel J;Bowen A;Braxton JR;Chen J;Chio CM;Chio US;Deshpande I;Doan L;Faust B;Flores S;Jin M;Kim K;Lam VL;Li F;Li J;Li YL;Li Y;Liu X;Lo M;Lopez KE;Melo AA;Moss FR 3rd;Nguyen P;Paulino J;Pawar KI;Peters JK;Pospiech TH Jr;Safari M;Sangwan S;Schaefer K;Thomas PV;Thwin AC;Trenker R;Tse E;Tsui TKM;Wang F;Whitis N;Yu Z;Zhang K;Zhang Y;Zhou F;Saltzberg D;QCRG Structural Biology Consortium;Hodder AJ;Shun-Shion AS;Williams DM;White KM;Rosales R;Kehrer T;Miorin L;Moreno E;Patel AH;Rihn S;Khalid MM;Vallejo-Gracia A;Fozouni P;Simoneau CR;Roth TL;Wu D;Karim MA;Ghoussaini M;Dunham I;Berardi F;Weigang S;Chazal M;Park J;Logue J;McGrath M;Weston S;Haupt R;Hastie CJ;Elliott M;Brown F;Burness KA;Reid E;Dorward M;Johnson C;Wilkinson SG;Geyer A;Giesel DM;Baillie C;Raggett S;Leech H;Toth R;Goodman N;Keough KC;Lind AL;Zoonomia Consortium;Klesh RJ;Hemphill KR;Carlson-Stevermer J;Oki J;Holden K;Maures T;Pollard KS;Sali A;Agard DA;Cheng Y;Fraser JS;Frost A;Jura N;Kortemme T;Manglik A;Southworth DR;Stroud RM;Alessi DR;Davies P;Frieman MB;Ideker T;Abate C;Jouvenet N;Kochs G;Shoichet B;Ott M;Palmarini M;Shokat KM;García-Sastre A;Rassen JA;Grosse R;Rosenberg OS;Verba KA;Basler CF;Vignuzzi M;Peden AA;Beltrao P;Krogan NJ
通讯作者：
Krogan NJ
影响因子：
5.6
作者：
Bravo-Caparros, Inmaculada;Perazzoli, Gloria;Rafael Nieto, Francisco
通讯作者：
Rafael Nieto, Francisco
DOI：
10.1073/pnas.93.15.8072
发表时间：
1996-07-23
影响因子：
11.1
作者：
Hanner, M;Moebius, FF;Glossmann, H
通讯作者：
Glossmann, H
影响因子：
5.6
作者：
Cirino, Thomas J.;Eans, Shainnel O.;McLaughlin, Jay P.
通讯作者：
McLaughlin, Jay P.