title: Non-xanthine heterocycles: activity as antagonists of A1- and A2-adenosine receptors.
abstract: A variety of non-xanthine heterocycles were found to be antagonists of binding of [3H]phenylisopropyladenosine to rat brain A1-adenosine receptors and of activation of adenylate cyclase via interaction of N-ethylcarboxamidoadenosine with A2-adenosine receptors in human platelet and rat phenochromocytoma cell membranes. The pyrazolopyridines tracazolate, cartazolate and etazolate were several fold more potent than theophylline at both A1- and A2-adenosine receptors. The pyrazolopyridines, however, were still many fold less potent than 8-phenyltheophylline and other 8-phenyl-1,3-dialkylxanthines. A structurally related N6-substituted 9-methyladenine was also a potent adenosine antagonist with selectivity for A1 receptors. None of several aryl-substituted heterocycles, including a thiazolopyrimidine, imidazopyridines, benzimidazoles, a pyrazoloquinoline, a mesoionic xanthine analog and a triazolopyridazine exhibited the high potency typical of 8-phenyl-1,3-dialkylxanthines. A furyl-substituted triazoloquinazoline was very potent at both A1 and A2 receptors. A pteridin-2,4-dione, 1,3-dipropyllumazine, was somewhat less potent than theophylline at A1- and A2-adenosine receptors, whereas 1,3-dimethyllumazine was much less potent. A benzopteridin-2,4-dione, alloxazine, was somewhat more potent than theophylline. Other heterocycles with antagonist activity were the dibenzazepine carbamazepine and beta-carboline-3-ethyl carboxylate. The phenylimidazoline clonidine had no activity, whereas a related dihydroxyphenylimidazoline was a weak non-competitive adenosine antagonist.
authors.affiliation: Laboratory of Chemistry and Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, MD 20892.
authors.forename: J W
authors.initials: JW
authors.lastname: Daly
authors.forename: O
authors.initials: O
authors.lastname: Hong
authors.forename: W L
authors.initials: WL
authors.lastname: Padgett
authors.forename: M T
authors.initials: MT
authors.lastname: Shamim
authors.forename: K A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: D
authors.initials: D
authors.lastname: Ukena
mesh_terms: D000241:Adenosine / Q000037:antagonists & inhibitors*; D000818:Animals; D002243:Carbolines / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects; D011983:Receptors, Purinergic / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D002243:Carbolines; D006571:Heterocyclic Compounds; D007093:Imidazoles; D011725:Pyridines; D011963:Receptors, GABA-A; D011983:Receptors, Purinergic; D000241:Adenosine