IUPHAR themed review: Opioid efficacy, bias, and selectivity.
IUPHAR themed review: Opioid efficacy, bias, and selectivity.
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DOI：
10.1016/j.phrs.2023.106961
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发表时间：
2023-11
影响因子：
9.3
通讯作者：
Majumdar, Susruta
中科院分区：
文献类型：
--
作者：
Ramos-Gonzalez, Nokomis;Paul, Barnali;Majumdar, Susruta
作用于阿片受体家族的药物在临床上用于治疗慢性和急性疼痛，尽管它们代表了GABA类似物、抗抑郁药和SSRI之后的第二线治疗。在阿片家族中，mu和kappa阿片受体通常是靶向的。然而，μ阿片受体的激活具有便秘、耐受、依赖、欣快和呼吸抑制的副作用; κ阿片受体的激活导致烦躁和镇静。μ阿片受体激活的副作用导致μ受体药物被广泛滥用，具有极大的过量风险。由于这些原因，对更新更安全的阿片类镇痛剂的需求很高。多年来，阿片类药物领域的一个焦点是寻找在μ阿片受体处激活G蛋白途径而不激活β-抑制蛋白途径的药物，称为偏性激动。最近的进展表明，这可能不是在μ阿片受体上开发更安全的镇痛药的方法，尽管在κ阿片受体上仍然有一些希望。在这里，我们讨论了最近的新方法，以开发更安全的阿片类药物，包括疗效与偏见和微调受体激活的靶向亚口袋中的正构网站，我们探讨了最近的工作的结构基础上的偏见，我们提出的建议，Gα亚型的选择性可能是一个令人兴奋的新领域的兴趣。
Drugs acting at the opioid receptor family are clinically used to treat chronic and acute pain, though they represent the second line of treatment behind GABA analogs, antidepressants and SSRI’s. Within the opioid family mu and kappa opioid receptor are commonly targeted. However, activation of the mu opioid receptor has side effects of constipation, tolerance, dependence, euphoria, and respiratory depression; activation of the kappa opioid receptor leads to dysphoria and sedation. The side effects of mu opioid receptor activation have led to mu receptor drugs being widely abused with great overdose risk. For these reasons, newer safer opioid analgesics are in high demand. For many years a focus within the opioid field was finding drugs that activated the G protein pathway at mu opioid receptor, without activating the β-arrestin pathway, known as biased agonism. Recent advances have shown that this may not be the way forward to develop safer analgesics at mu opioid receptor, though there is still some promise at the kappa opioid receptor. Here we discuss recent novel approaches to develop safer opioid drugs including efficacy vs bias and fine-tuning receptor activation by targeting sub-pockets in the orthosteric site, we explore recent works on the structural basis of bias, and we put forward the suggestion that Gα subtype selectivity may be an exciting new area of interest.
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影响因子：
4
作者：
Bonezzi C;Fornasari D;Cricelli C;Magni A;Ventriglia G
通讯作者：
Ventriglia G
影响因子：
56.9
作者：
Bohn, LM;Lefkowitz, RJ;Lin, FT
通讯作者：
Lin, FT
影响因子：
4.6
作者：
Burgueño J;Pujol M;Monroy X;Roche D;Varela MJ;Merlos M;Giraldo J
通讯作者：
Giraldo J
影响因子：
16
作者：
Cong X;Maurel D;Déméné H;Vasiliauskaité-Brooks I;Hagelberger J;Peysson F;Saint-Paul J;Golebiowski J;Granier S;Sounier R
通讯作者：
Sounier R
影响因子：
7.3
作者：
Chakraborty S;Uprety R;Slocum ST;Irie T;Le Rouzic V;Li X;Wilson LL;Scouller B;Alder AF;Kruegel AC;Ansonoff M;Varadi A;Eans SO;Hunkele A;Allaoa A;Kalra S;Xu J;Pan YX;Pintar J;Kivell BM;Pasternak GW;Cameron MD;McLaughlin JP;Sames D;Majumdar S
通讯作者：
Majumdar S