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烟云听雨铁杆木虫 (正式写手)
金虫
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[求助]
求翻译一段英文文献（药化）
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Following selective secondary binding evaluation for κ opioid and sigma binding, we noted that many compounds of this chemotype possessed potent sigma 1 receptor binding. Although full panel GPCR screening was not completed for this chemotype, six compounds (entries 1–3, 5, 6, and 14 in Table 1) were found to lack submicromolar binding against 5HT6 and D4 (arbitrarily chosen as representative countertargets). Five individual examples of compounds with a single digit nanomolar sigma 1 Ki value were found (entries 2, 3, 7, 15, and 20). In particular, entry 20 was an exciting result, due to both potency (2 nM Ki) and selectivity (sigma 1:sigma 2:KOR binding ratio of 1∶88∶558). Also of note was that the stereochemistry of the ethyl side chain has little effect on this potent sigma binding because derivatives of both epimers were similarly tight-binding. The sigma 1 secondary binding curves for the compounds in entries 19, 20, and the control compound, haloperidol, are shown in Fig. 5. The binding curves illustrate the dramatic link between activity and basic nitrogen incorporation with compound 10{20}, found to be of comparable potency to haloperidol, and compound 10{19}, found to be inactive. An analogous trend was observed for the sigma 2 binding between these compounds, although with a less drastic dependence on basic nitrogen incorporation. Although the structures of 10{20} and haloperidol differ substantially in connectivity, both contain a phenyl group tethered to the basic nitrogen. To assess whether the tricyclic scaffold is contributing significantly to the observed binding activity, the alkyl chain analogue was synthesized (entry 22). Gratifyingly, this analogue retained marked sigma binding affinity, thus dispelling any speculation that an aromatic moiety tethered amine is responsible for the activity. |
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