Synthesis of Isoquinoline Analogues Modeled after Higenamine

去甲基烏藥鹼修飾之異喹啉類似物合成研究

陳繼明(Chi-Ming Chen) ； 羅吉方(Chi-Fang Lo)

《藥物食品檢驗局調查研究年報》 9號 (1991/09) Pp. 431-444

https://doi.org/10.6946/ASRNL.199109.0431

摘要

消旋去甲基烏藥鹼(Ia)為附子或烏頭之強心成分，作用甚強，本研究室前曾證明去甲基烏藥鹼對於交感神經乙型受容體具有立體選擇的藥效，左旋體遠比右旋體為強。今就以去甲基烏藥鹼分子經化學合成修飾製備七種化合物，於交感神經受容體評估做為構造及作用關係的探討。
依據一般benzylisoquinoline或phenylisoquinoline的化學合成方法，七種異喹啉(Ib-Ih)之衍生物經化學合成製備後，以天竺鼠之離體左心房肌以及氣管平滑肌做為藥理試驗對象。除了化合物Id外，其餘各化合物於β1及β2受容體作用結果均比天然之去甲基烏藥鹼為弱。但是Id發現對於支氣管平滑肌鬆弛作用比去甲基烏藥鹼為佳。化合物Ib及Ic雖無效，但是具有類似propranolol交感神經乙型受容體拮抗藥效。本實驗初步結果發現，對於去甲基烏藥鹼分子之藥效，catechol基是必備無疑；而異喹啉環的碳－1位置上取代的p-hydroxybenzyl基對於藥效有非常大的影響；至於其立體化學的配位是有立體選擇性的。

並列摘要

Demethylcoclaurine (higenamine) (Ia), a potent cardiotonic alkaloid, was isolated from Aconiti root as a racemic mixture. Previously, (-)-higenamine was demonstrated to have a stereoselective preference over (+)-higenamine in both beta-1 and beta-2 adrenergic activities. This paper reports the structure-activity relationship study on the several analogues modeled after higenamine and the evaluations on the beta adrenergic activities. Following the usual synthetic procedures for benzylisoquinolines and phenylisoquinolines by Bischler-Napieralski and Pictet-Spengler reactions, seven compounds (Ib-Ih) were prepared and then tested on left atria and tracheal muscle of guinea pig to evaluate their cardiac stimulation and tracheal relaxation activity. All the compounds except Id were either inactive or less active than natural higenamine. Compound Id was shown to have better activity in tracheal dilation than higen amine. In addition, compound lb and Ic were demonstrated to possess a weak beta adrenergic blocking effect. In conclusion, a catechol moiety is presumably to be essential for its activity and substitution of the p-hydroxybenzyl group at C-1 position with correct stereochemistry in the isoquinoline molecule makes a great contribution to the activation of beta adrenergic receptors.

並列關鍵字

Higenamine ； Isoquinoline analogues ； Adrenergic β1& β2 activity