In 2013,Gregory, Karen J.; Nguyen, Elizabeth D.; Reiff, Sean D.; Squire, Emma F.; Stauffer, Shaun R.; Lindsley, Craig W.; Meiler, Jens; Conn, P. Jeffrey published 《Probing the metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulator (PAM) binding pocket: discovery of point mutations that engender a “”molecular switch”” in PAM pharmacology》.Molecular Pharmacology published the findings.Name: Azetidin-3-ol hydrochloride The information in the text is summarized as follows:
Pos. allosteric modulation of metabotropic glutamate receptor subtype 5 (mGlu5) is a promising novel approach for the treatment of schizophrenia and cognitive disorders. Allosteric binding sites are topog. distinct from the endogenous ligand (orthosteric) binding site, allowing for co-occupation of a single receptor with the endogenous ligand and an allosteric modulator. Neg. allosteric modulators (NAMs) inhibit and pos. allosteric modulators (PAMs) enhance the affinity and/or efficacy of the orthosteric agonist. The mol. determinants that govern mGlu5 modulator affinity vs. cooperativity are not well understood. Focusing on the modulators based on the acetylene scaffold, the authors sought to determine the mol. interactions that contribute to PAM vs. NAM pharmacol. Generation of a comparative model of the transmembrane-spanning region of mGlu5 served as a tool to predict and interpret the impact of mutations in this region. Application of an operational model of allosterism allowed for determination of PAM and NAM affinity estimates at receptor constructs that possessed no detectable radioligand binding as well as delineation of effects on affinity vs. cooperativity. Novel mutations within the transmembrane domain (TM) regions were identified that had differential effects on acetylene PAMs vs. 2-methyl-6-(phenylethynyl)-pyridine, a prototypical NAM. Three conserved amino acids (Y658, T780, and S808) and two non-conserved residues (P654 and A809) were identified as key determinants of PAM activity. Interestingly, the authors identified two point mutations in TMs 6 and 7 that, when mutated, engender a mode switch in the pharmacol. of certain PAMs. In the part of experimental materials, we found many familiar compounds, such as Azetidin-3-ol hydrochloride(cas: 18621-18-6Name: Azetidin-3-ol hydrochloride)
Azetidin-3-ol hydrochloride(cas:18621-18-6) is one of azetidine.Azetidines (azacyclobutanes) constitute a well-known class of heterocyclic compounds. Azetidine scaffold has been discovered in several natural products.Name: Azetidin-3-ol hydrochloride Several pharmacologically important synthetic compounds also contain azetidine ring. Because of inherent ring strain, the synthesis of azetidines is a challenging endeavor.
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