Discovery of AD258 as a Sigma Receptor Ligand with Potent Antiallodynic Activity.
Discovery of AD258 as a Sigma Receptor Ligand with Potent Antiallodynic Activity.
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DOI：
10.1021/acs.jmedchem.3c00959
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发表时间：
2023-08-24
影响因子：
7.3
通讯作者：
Amata, Emanuele
中科院分区：
文献类型：
--
作者：
Dichiara, Maria;Ambrosio, Francesca Alessandra;Lee, Sang Min;Ruiz-Cantero, M. Carmen;Lombino, Jessica;Coricello, Adriana;Costa, Giosue;Shah, Dhara;Costanzo, Giuliana;Pasquinucci, Lorella;Son, Kyung No;Cosentino, Giuseppe;Gonzalez-Cano, Rafael;Marrazzo, Agostino;Aakalu, Vinay Kumar;Cobos, Enrique J.;Alcaro, Stefano;Amata, Emanuele
设计和合成一系列2,7-二氮杂螺[4.4]壬烷衍生物作为有效的sigma受体（SR）配体，与镇痛活性相关，是本研究的重点。在本研究中，我们测量了S1R和S2R的亲和力，并通过分子建模研究了结合位姿特征。最有希望的化合物进行体外毒性测试，随后筛选体内镇痛特性。化合物9d （AD258）在体外细胞毒性可忽略，对两种SRs具有高结合亲和力（KiS1R = 3.5 nM, KiS2R = 2.6 nM），但对其他疼痛相关靶点没有结合亲和力，并且在辣椒素诱导的异速疼痛模型中发挥了很高的效力，在极低剂量（0.6-1.25 mg/kg）下达到最大的抗异速疼痛作用。功能活性实验表明，S1R拮抗作用是9d的作用所必需的，并且它不会引起运动损伤。此外，9d表现出良好的药代动力学特征。
The design and synthesis of a series of 2,7-diazaspiro[4.4]nonane derivatives as potent sigma receptor (SR) ligands, associated with analgesic activity, are the focus of this work. In this study, affinities at S1R and S2R were measured, and molecular modeling studies were performed to investigate the binding pose characteristics. The most promising compounds were subjected to in vitro toxicity testing and subsequently screened for in vivo analgesic properties. Compound 9d (AD258) exhibited negligible in vitro cellular toxicity and a high binding affinity to both SRs (KiS1R = 3.5 nM, KiS2R = 2.6 nM), but not for other pain-related targets, and exerted high potency in a model of capsaicin-induced allodynia, reaching the maximum antiallodynic effect at very low doses (0.6–1.25 mg/kg). Functional activity experiments showed that S1R antagonism is needed for the effects of 9d and that it did not induce motor impairment. In addition, 9d exhibited a favorable pharmacokinetic profile.
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影响因子：
5
作者：
Cifani C;Micioni Di Bonaventura E;Botticelli L;Del Bello F;Giorgioni G;Pavletić P;Piergentili A;Quaglia W;Bonifazi A;Schepmann D;Wünsch B;Vistoli G;Micioni Di Bonaventura MV
通讯作者：
Micioni Di Bonaventura MV
神经系统疾病中的 Sigma-1 受体调节神经炎症。
影响因子：
5.3
作者：
Jia J;Cheng J;Wang C;Zhen X
通讯作者：
Zhen X
影响因子：
4.2
作者：
Amata, Emanuele;Dichiara, Maria;Prezzavento, Orazio
通讯作者：
Prezzavento, Orazio
影响因子：
4.6
作者：
Gris G;Portillo-Salido E;Aubel B;Darbaky Y;Deseure K;Vela JM;Merlos M;Zamanillo D
通讯作者：
Zamanillo D
影响因子：
7.3
作者：
Hiesinger, Kerstin;Dar'in, Dmitry;Krasavin, Mikhail
通讯作者：
Krasavin, Mikhail