Further studies regarding the structure activity relationships of beta-adrenoceptor antagonists

1. The ortho (M66,527) and para (M66,368) analogues of 1-t-butylamino-3-(methoxyphenoxy)-2-propanol and para substituted tertiary butylphenoxy-1-N-isopropylamine-3 propanol-2 oxalate acid (L8429) were tested in dogs for their beta-adrenoceptor blocking activity.2. M66,527, which contains a methoxy group in the ortho position of the benzene ring, was found to be comparable to propranolol in blocking cardiac and peripheral vascular responses to isoprenaline. Like propranolol, M66,527 was more potent on peripheral receptors.3. Transference of the methoxy group to the para position (M66,368) reduced the overall potency; however, this compound was found to be relatively cardioselective in that it was 2 to 3.6 times more active in blocking cardiac responses to isoprenaline.4. The cardioselective properties of the short chain para methoxy substituent were less than those reported for compounds with longer para substitutions (i.e. practolol, para oxprenolol and para alprenolol).5. L8429, with a tertiary butyl group in the para position, was a weak beta-adrenoceptor antagonist without cardioselective properties. A longer, less bulky n-butyl group may provide for a more potent and selective antagonist.6. The results support the view that the size and site of the substituent on the benzene ring may be of importance in determining the cardioselective potency of beta-adrenoceptor antagonists.