Structure-activity profile of a series of novel triazoloquinazoline adenosine antagonists

During a search for benzodiazepine receptor modulators, a highly potent adenosine antagonist (CGS 15943) was discovered. The compound was defined as a resonance-stabilized hybrid of the canonical structures 9-chloro-2-(2-furyl)[1,2,4]triazolo[1,5-c]quinazolin-5-amine (2a) and 9-chloro-2-(2-furyl)-5,6-dihydro[1,2,4]triazolo[1,5-c]-quinazolin- 5-imine (2b). Spectroscopic evidence and chemical reactivity in polar media favor the amine form 2a as the major contributor of the two canonical structures. The synthesis of 2 and some of its analogues and the structure-activity relationships in four biological test systems are described. Replacement of the 9-chloro group by hydrogen, hydroxyl, or methoxyl gave compounds with comparable binding potency at the A1 and A2 receptors but much less activity as antagonists of 2-chloroadenosine in guinea pig tracheal strips. Alkylation of the 5-amino group caused, in general, a loss of binding activity, particularly at the A2 receptor, as well as complete loss of activity in the tracheal model. Modification of the 2-furyl group caused a pronounced loss of activity in all of the test systems.