Synthesis of 1-(aminomethyl)-1,2,3,4-tetrahydroisoquinolines and their actions at adrenoceptors in vivo and in vitro.

An improved synthesis of 1-(aminomethyl)-1,2,3,4-tetrahydroisoquinolines has been developed by using aluminum hydride reduction of 1-cyano-1,2,3,4-tetrahydroisoquinolines. Three 1-(aminomethyl)-6,7-dihydroxytetrahydroisoquinolines were tested for actions at beta adrenoceptors in order to examine a proposed similarity between this series and the related phenylethanolamines. The aminomethyl, (isopropylamino)methyl, and (tert-butylamino)methyl derivatives all showed weak partial agonist activity at beta adrenoceptors and the first also showed weak alpha adrenoceptor agonist activity in vivo. Their low potency implies that the catechol group of THIQ sympathomimetics, such as trimetoquinol, binds differently from that of the natural catecholamines. The protonation behavior of representative aminomethyl-THIQ's was investigated by pKa measurement and 1H and 13C NMR, and the compounds were shown to be substantially monoprotonated, on the exocyclic nitrogen, at physiological pH.