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Affinity Labels for β-Adrenoreceptors: Preparation and Properties of Alkylating β-Blockers Derived from Indole
Pitha, Josef,Buchowiecki, Wieslaw,Milecki, Jan,Kusiak, John W.
, p. 612 - 615 (2007/10/02)
New alkylating ligands derived from indole with high affinity for β-adrenoceptors were synthesized and their properties examined.N8-(Bromoacetyl)-N1--(Z)-1,8-diamino-p-menthane (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-menthane.A similar reaction employing 2-cyano-4-indolyl glycidyl ether yielded the respective cyano derivatives 10 and 11.Apparent affinities (Ki, M) for β-adrenoreceptors on membrane preparations from rat heart and lung were 4.6*10-10 and 1.34*10-9 for 8, 2.3*10-8 and 4.5*10-9 for 9, 6.1*10-10 and 1.49*10-9 for 10, and 1.83*10-9 and 2.78*10-9 for 11, respectively.When membranes were preincubated with the above ligands (1*10-8 M, 30 min, 30 deg C) and then washed extensively, reduction in the concentration of specific binding sites of dihydroalprenolol ranged from 7percent to 76percent and there was no change in KD of the remaining binding sites. (+/-)-Alprenolol and (-)-isoproterenol, but not (+)-isoproterenol, when included with the alkylating ligands in the preincubation mixtures, prevented the reduction in concentration of 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*10-9 and 60*10-9 M.These results suggest that high-affinity irreversible β-adrenergic antagonists were obtained that may be useful for in vivo studies of β-adrenoceptors.
