合成新穎性1,5-芳基取代吡咯及結構活性探討做為大麻類接收器CB1配基

Synthesis and Structure-activity Relationship Study of Novel 1,5-Diarylpyrrole as Potent and Selective CB1 Cannabinoid Receptor Ligands

吳慧娟

指導教授 ： 林俊成

國立清華大學/理學院/化學系/博士(2014年)

摘要

我們以帕爾-克諾爾反應(Paal-Knorr reaction)建構出一系列具有CB1接收器配基的吡咯(pyrrole)結構，並且對於新穎的1,5-二芳基吡咯醯胺CB1接收器配基其結構與活性的關聯性進行探討。具有（R）-1 - 羥基-3-甲基 - 1,1-二芳基-2-丁基吡咯醯胺化合物72 (IC50 = 4.2 nM) 與96 (IC50 = 1.9 nM) 對於CB1接收器具有高親和性與選擇性。具有環己基的吡咯醯胺64 (IC50 = 15.2 nM) 和94 (IC50 = 14.3 nM) 對於CB1接收器具有高親和性。此外，具有終端乙炔取代基的C-3醯胺吡咯化合物,其化合物包含了對稱與不對稱顯的烷基均對於CB1接收器有高親和力，而這些化合物包括了64，75，77，79和80。這些結果建議吡咯醯胺41和42可能是能夠對於CB1提供理化優勢的候選化合物。
具有環己基終端乙炔取代基的C-3的醯胺吡唑化合物104 (CB1 IC50 = 12.0 nM) 同樣顯現出對CB1接收器有高親和力，此種現象指出在CB1接收器在不活耀的狀態下，終端乙炔取代基不尋常地增強接收器與配基之間的作用。

關鍵字

CB1接收器配基 ； 減肥藥

並列摘要

ABSTRACT
A series of pyrrole structure-based CB1 receptor ligands was constructed by the Paal-Knorr reaction. Pyrrole amides 72 and 96, which were substituted with (R)-1-hydroxy-3-methyl-1,1-diphenylbutan-2-yl, exhibited high affinity and excellent selectivity for CB1 receptor (IC50 = 4.2 nM and 1.9 nM, respectively). The presence of cyclohexyl group on pyrrole amides 64 (IC50 = 15.2 nM) and 94 (IC50 = 14.3 nM) also showed promising binding affinity enhancement to CB1 receptor. Moreover, C3-carboxamides of pyrrole compounds substituted with terminal ethyne, which contain not only symmetric dialkyl group but also one long alkyl chain such as 75, 77, 79, and 80 demonstrated high CB1 binding affinity. These results suggested that pyrrole amides 41 and 42 might become candidates to provide physicochemical benefits towards CB1. Compound 104 (IC50 = 12.0 nM for CB1), a pyrazole derivative by replacement of rimonabant C-3 group with cyclohexylethynyl amide, shows the same affinity as rimonabant C-3 for CB1 receptor, indicating that terminal ethyne unit provides unusual enhancement of receptor-ligand interaction to inactivate CB1 receptor.

Key Words: Rimonabant; Anti-Obesity agents; CB1-antagonists; Pyrrole; Metabolic syndrome therapy; receptor blockers

參考文獻

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