Bronchoselective actions of a new series of trimetoquinol analogues

In selected beta 1- (guinea pig atrial) and beta 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-alpha-methylbenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (alpha-methylTMQ), alpha-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-alpha-methylTMQ greater than (+/-)-TMQ greater than ISO greater than erythro-alpha-methylTMQ greater than N-methylTMQ greater than alpha-dimethylTMQ. Only N-methylTMQ gave an intrinsic activity similar to ISO, whereas the alpha-methylated TMQ analogues were partial agonists in this beta 2-system. In atria, the rank order of beta 1-potency was ISO greater than (+/-)-TMQ greater than threo-alpha-methylTMQ greater than N-methylTMQ = erythro-alpha-methylTMQ. Maximal chronotropic effects of all compounds, with the exception of threo-alpha-methylTMQ, were similar to ISO in this preparation. Both alpha-dimethylTMQ and open chain dimethylTMQ analogues were inactive as agonists in this beta 1-system. The ratio of beta 2 : beta 1 selectivity (trachea vs. atria), relative to ISO for threo-alpha-methylTMQ, erythro-alpha-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 greater than threo-alpha-methylTMQ = TMQ greater than erythro-alpha-methylTMQ, the comparative beta 2-selectivity (lung parenchyma vs. atria) relative to ISO, for erythro-alpha-methylTMQ, threo-alpha-methylTMQ and TMQ was 2.5, 1.9 and 0.24, respectively. It is concluded that lipophilic substitutions on the alpha-carbon of the 1-(3,4,5-trimethoxybenzyl)-substituent of TMQ can generate compounds which are potent bronchoselective adrenoceptor agonists. Threo-alpha-methylTMQ and erythro-alpha-methylTMQ were more beta 2-selective than (+/-)-TMQ.