Affinity labels for .beta.-adrenoceptors: preparation and properties of alkylating .beta.-blockers derived from indole

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Abstract
New alkylating ligands derived from indole with high affinity for .beta.-adrenoceptors were synthesized and their properties examined. N8-(Bromoacetyl)-N1-[3-(4-indolyloxy)-2-hydroxypropyl]-(Z)-1,8-diamino-p-methane (8) and its N1,N8 isomer (9) were prepared by the reaction of bromoacetyl bromide with a product of the condensation of 4-indolyl glycidyl ether with (Z)-1,8-diamino-p-methane. A similiar reaction employing 2-cyano-4-indolyl glycidyl ether yielded the respective cyano derivatives 10 and 11. Apparent affinities (Ki,M) for .beta.-adrenoceptors on membrane preparations from rat heart and lung were 4.6 .times. 10-10 and 1.34 .times. 10-9 for 8, 2.3 .times. 10-8 and 4.5 .times. 10-9 for 9, 6.1 .times. 10-10 and 1.49 .times. 10-9 for 10, and 1.83 .times. 10-9 and 2.78 .times. 10-9 for 11, respectively. When membranes were preincubated with the above ligands (1 .times. 10-8 M, 30 min, 30.degree.C) and then washed extensively, reduction in the concentration of specific binding sites of [3H]dihydroalprenolol ranged from 7% to 76% and there was no change in KD of the remaining binding sites. (.+-.)-Alprenolol and (-)-isoproterenol, but not (+)-isoproterenol, when included with the alkaylating ligands in the preincubation mixtures, prevented the reduction in concentration of [3H]dihydroalprenolol binding sites. Compounds 8-11 alone did not stimulate adenylate cyclase activity in rat heart homogenates. However, these compounds inhibited (-)-isoproterenol-stimulated adenylate cyclase activity with Ki values ranging between 5 .times. 10-9 and 60 .times. 10-9M. These results suggest that high-affinity irreversible .beta.-adrenergic antagonists were obtained that may be useful for in vivo studies of .beta.-adrenoceptors.

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