Synthesis of Isoquinoline Analogues Modeled after Higenamine

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 higenamine. In addition, compound Ib 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.