Bronchoselective actions of a new series of trimetoquinol analogues

Abstract

In selected β 1-(guinea pig atria) and β 2-(guinea pig trachea and lung parenchyma) adrenoceptor systems, we have examined the interaction of isoproterenol (ISO), trimetoquinol (TMQ), erythro- and threo-diastereoisomers of 1-(3,4,5-trimethoxy-α-methylbenzyl)-6,7-dihydroxy- 1,2,3,4-tetrahydroisoquinoline (α-methylTMQ), α-dimethylTMQ, N-methylTMQ and N-[2-methyl-2-(3,4,5- trimethoxyphenyl)propyl]dopamine (open chain dimethylTMQ analogue). The rank order of potency for agonists in trachea was threo- α-methylTMQ>(±)-TMQ>ISO>erythro- α-methylTMQ>N-methylTMQ> α-dimethylTMQ. Only N-methylTMQ gave an intrinsic activity similar to ISO, whereas the α-methylated TMQ analogues were partial agonists in this β 2-system. In atria, the rank order of β 1-potency was ISO>(±)-TMQ>threo-α-methylTMQ>N-methylTMQ=erythro- α-methylTMQ. Maximal chronotr effects of all compounds, with the exception of threo-α-methylTMQ, were similar to ISO in this preparation. Both α-dimethylTMQ and open chain dimethylTMQ analogues were inactive as agagonists in this β 1-system. The ratio of β 2: β 1 selectivity (trach atria), relative to ISO for threo-α-methylTMQ, erythro-α-methylTMQ, TMQ and N-methylTMQ was 106.5, 27, 7 and 5.8, respectively. Whereas the rank order of potency for selected compounds in lung parenchyma was ISO>threo- α-methylTMQ=TMQ>erythro- α- methylTMQ, the comparative β 2-selectivity (lung parenchyma vs. atria) relative to ISO, for erythro-α-methylTMQ, threo-α-methylTM and TMQ was 2.5, 1.9 and 0.24, respectively. It is concluded that lipophilic substitutions on the α-carbon of the 1-(3,4,5- trimethoxybenzyl)-substituent of TMQ can generate compounds which are potent bronchoselective adrenoceptor agonists. Threo-α- methylTMQ and erythro-α-methylTMQ were more β 2-selective than (±)-TMQ.