The authors report the structural characterization of M4R selective allosteric agonist, compound-110, as well as agonist iperoxo and positive allosteric modulator LY2119620. The cryo-EM structures of compound-110, ipe...
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The authors report the structural characterization of M4R selective allosteric agonist, compound-110, as well as agonist iperoxo and positive allosteric modulator LY2119620. The cryo-EM structures of compound-110, iperoxo or iperoxo-LY2119620 bound M4R-Gi complex reveal different interaction modes and activation mechanisms of M4R. An antipsychotic activity of compound-110 with low extrapyramidal side effects in a schizophrenia-mimic mouse model is also reported. Thus, the study provides structural insights for selectively targeting mAChRs subtypes. Muscarinic acetylcholine receptors (mAChRs) respond to the neurotransmitter acetylcholine and play important roles in human nervous system. Muscarinic receptor 4 (M4R) is a promising drug target for treating neurological and mental disorders, such as Alzheimer's disease and schizophrenia. However, the lack of understanding on M4R's activation by subtype selective agonists hinders its therapeutic applications. Here, we report the structural characterization of M4R selective allosteric agonist, compound-110, as well as agonist iperoxo and positive allosteric modulator LY2119620. Our cryo-electron microscopy structures of compound-110, iperoxo or iperoxo-LY2119620 bound M4R-G(i) complex reveal their different interaction modes and activation mechanisms of M4R, and the M4R-ip-LY-G(i) structure validates the cooperativity between iperoxo and LY2119620 on M4R. Through the comparative structural and pharmacological analysis, compound-110 mostly occupies the allosteric binding pocket with vertical binding pose. Such a binding and activation mode facilitates its allostersic selectivity and agonist profile. In addition, in our schizophrenia-mimic mouse model study, compound-110 shows antipsychotic activity with low extrapyramidal side effects. Thus, this study provides structural insights to develop next-generation antipsychotic drugs selectively targeting on mAChRs subtypes.
Long and thin In2O3/ZnO heterostructured microbelts were synthesized by sol-gel combined with electrospinning process. The as-prepared microbelts show the well defined one-dimensional belt structures with 1-5 mu m in ...
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Long and thin In2O3/ZnO heterostructured microbelts were synthesized by sol-gel combined with electrospinning process. The as-prepared microbelts show the well defined one-dimensional belt structures with 1-5 mu m in width and tens of millimeters in length. The polycrystalline microbelts calcined at 973 K for 1 h are still continuous and have the uniform rectangular cross sections and the thickness to width ratio is around 1:10. The crystalline phases of samples are investigated by X-ray diffraction and the morphology is examined using transmission electron microscope and scanning electron microscope. In2O3/ZnO heterostructured microbelts exhibit the excellent visible photocatalytic property in the photodegradation of methyl orange (MO), and over 94 % of MO was degraded within 3 h.
Drugs frequently require interactions with multiple targets-via a process known as poly-pharmacology-to achieve their therapeutic actions. Currently, drugs targeting several serotonin receptors, including the 5-HT2C r...
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Drugs frequently require interactions with multiple targets-via a process known as poly-pharmacology-to achieve their therapeutic actions. Currently, drugs targeting several serotonin receptors, including the 5-HT2C receptor, are useful for treating obesity, drug abuse, and schizophrenia. The competing challenges of developing selective 5-HT2C receptor ligands or creating drugs with a defined poly-pharmacological profile, especially aimed at G protein-coupled receptors (GPCRs), remain extremely difficult. Here, we solved two structures of the 5-HT2C receptor in complex with the highly promiscuous agonist ergotamine and the 5-HT2A-C receptor-selective inverse agonist ritanserin at resolutions of 3.0 angstrom and 2.7 angstrom, respectively. We analyzed their respective binding poses to provide mechanistic insights into their receptor recognition and opposing pharmacological actions. This study investigates the structural basis of polypharmacology at canonical GPCRs and illustrates how understanding characteristic patterns of ligand-receptor interaction and activation may ultimately facilitate drug design at multiple GPCRs.
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