دورية أكاديمية
Synthesis of selective agonists for the α7 nicotinic acetylcholine receptor with in situ click-chemistry on acetylcholine-binding protein templates.
| العنوان: | Synthesis of selective agonists for the α7 nicotinic acetylcholine receptor with in situ click-chemistry on acetylcholine-binding protein templates. |
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| المؤلفون: | Yamauchi JG; Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA., Gomez K, Grimster N, Dufouil M, Nemecz A, Fotsing JR, Ho KY, Talley TT, Sharpless KB, Fokin VV, Taylor P |
| المصدر: | Molecular pharmacology [Mol Pharmacol] 2012 Oct; Vol. 82 (4), pp. 687-99. Date of Electronic Publication: 2012 Jul 11. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Pharmacology and Experimental Therapeutics Country of Publication: United States NLM ID: 0035623 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-0111 (Electronic) Linking ISSN: 0026895X NLM ISO Abbreviation: Mol Pharmacol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Bethesda, MD : American Society for Pharmacology and Experimental Therapeutics |
| مواضيع طبية MeSH: | Carrier Proteins/*chemistry , Nicotinic Agonists/*chemical synthesis , Receptors, Nicotinic/*metabolism, Alkynes/chemical synthesis ; Alkynes/chemistry ; Alkynes/pharmacology ; Animals ; Aplysia ; Azides/chemical synthesis ; Azides/chemistry ; Azides/pharmacology ; Carrier Proteins/genetics ; Cell Line ; Click Chemistry ; Humans ; Lymnaea ; Mice ; Mutation ; Nicotinic Agonists/chemistry ; Nicotinic Agonists/pharmacology ; Nicotinic Antagonists/chemical synthesis ; Nicotinic Antagonists/chemistry ; Nicotinic Antagonists/pharmacology ; Radioligand Assay ; Stereoisomerism ; Structure-Activity Relationship ; Triazoles/chemical synthesis ; Triazoles/chemistry ; Triazoles/pharmacology ; Tropanes/chemical synthesis ; Tropanes/chemistry ; Tropanes/pharmacology ; alpha7 Nicotinic Acetylcholine Receptor |
| مستخلص: | The acetylcholine-binding proteins (AChBPs), which serve as structural surrogates for the extracellular domain of nicotinic acetylcholine receptors (nAChRs), were used as reaction templates for in situ click-chemistry reactions to generate a congeneric series of triazoles from azide and alkyne building blocks. The catalysis of in situ azide-alkyne cycloaddition reactions at a dynamic subunit interface facilitated the synthesis of potentially selective compounds for nAChRs. We investigated compound sets generated in situ with soluble AChBP templates through pharmacological characterization with α7 and α4β2 nAChRs and 5-hydroxytryptamine type 3A receptors. Analysis of activity differences between the triazole 1,5-syn- and 1,4-anti-isomers showed a preference for the 1,4-anti-triazole regioisomers among nAChRs. To improve nAChR subtype selectivity, the highest-potency building block for α7 nAChRs, i.e., 3α-azido-N-methylammonium tropane, was used for additional in situ reactions with a mutated Aplysia californica AChBP that was made to resemble the ligand-binding domain of the α7 nAChR. Fourteen of 50 possible triazole products were identified, and their corresponding tertiary analogs were synthesized. Pharmacological assays revealed that the mutated binding protein template provided enhanced selectivity of ligands through in situ reactions. Discrete trends in pharmacological profiles were evident, with most compounds emerging as α7 nAChR agonists and α4β2 nAChR antagonists. Triazoles bearing quaternary tropanes and aromatic groups were most potent for α7 nAChRs. Pharmacological characterization of the in situ reaction products established that click-chemistry synthesis with surrogate receptor templates offered novel extensions of fragment-based drug design that were applicable to multisubunit ion channels. |
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| معلومات مُعتمدة: | U01-DA019372 United States DA NIDA NIH HHS; R01-GM087620 United States GM NIGMS NIH HHS; U01 DA019372 United States DA NIDA NIH HHS; R01 GM018360 United States GM NIGMS NIH HHS; T32 GM007752 United States GM NIGMS NIH HHS; R01-GM18360-39 United States GM NIGMS NIH HHS; R01 GM087620 United States GM NIGMS NIH HHS; T32-GM07752 United States GM NIGMS NIH HHS |
| المشرفين على المادة: | 0 (AChBP protein, Lymnaea) 0 (Alkynes) 0 (Azides) 0 (Carrier Proteins) 0 (Chrna7 protein, human) 0 (Chrna7 protein, mouse) 0 (Nicotinic Agonists) 0 (Nicotinic Antagonists) 0 (Receptors, Nicotinic) 0 (Triazoles) 0 (Tropanes) 0 (alpha7 Nicotinic Acetylcholine Receptor) |
| تواريخ الأحداث: | Date Created: 20120713 Date Completed: 20121221 Latest Revision: 20211021 |
| رمز التحديث: | 20221213 |
| مُعرف محوري في PubMed: | PMC3463225 |
| DOI: | 10.1124/mol.112.080291 |
| PMID: | 22784805 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1521-0111 |
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| DOI: | 10.1124/mol.112.080291 |