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烟云听雨铁杆木虫 (正式写手)
金虫
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Construction of a Follow-Up Library and Binding Studies. The observation that the majority of potent binding compounds possessed basic nitrogen prompted us to consider the construction of unique analogues containing alternative basic nitrogen heterocycles. The ideal method would furnish the heterocyclic products diastereoselectively with a minimum of manipulations and allow for independent functionalization at both the left- and righthand hemispheres on the core scaffold. During the scale-up of Stemona scaffolds for library synthesis, we noted that the tandem Diels–Alder/Schmidt reaction could be halted at the Diels–Alder stage and the azido diketone product isolated by judicious choice of Lewis acid and by limiting the number of equivalents added. This observation permitted us to investigate an alternative Diels– Alder/aza–Wittig reaction sequence that afforded the tricyclic skeleton 9, which contained an unmasked basic nitrogen amenable to alkylation or amidation as desired (Scheme 3). The scaffold readily participated in reductive amination with a diverse range of aldehydes to provide a collection of tertiary amines in this series. Given the precedent of diverse GPCR binding observed for the basic nitrogen-containing compounds previously profiled (see Figs. 3 and 4), we reasoned that this collection of compounds would afford interesting screening results. We were inclined toward screening against the opioid receptors and Sig-Rs based on the association of these receptors with antitussive activity (40, 41), and we began our profiling investigations with these. In addition to their potential as an antitussive target, Sig-Rs have been implicated in a wide range of physiological functions and thus represent a unique therapeutic target for disorders such as depression, schizophrenia, and Parkinson’s disease (41–44). Although the precise role of Sig-Rs is not well understood, it is widely believed that the effects of Sig-Rs can be attributed to their modulation of other receptor types. This neuromodulatory role has complicated research on Sig-Rs and underscores the benefit of finding new compounds to modulate these receptors and probe their function (43, 44). Table 1 summarizes the overall yields for the initial library efforts as well as exploratory screening for κ opioid receptor (KOR), sigma 1, and sigma 2 receptor binding (Ki values) for these compounds. |
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