1H-Imidazo[4,5-c]quinolin-4-amines: novel non-xanthine adenosine antagonists

Abstract

On the basis of a model we recently developed for the antagonist binding site of the adenosine A1 receptor (J. Med. Chem. 1990, 33, 1708-1713), it was predicted that 1H-imidazo[4,5-c]quinolin-4-amines would be antagonists of the A1 receptor. Furthermore, it was expected that certain hydrophobic substitutions at the 2- and 4-positions would enhance affinity. Here, we report on the synthesis and the adenosine A1 and A2 receptor affinity of substituted 1H-imidazo[4,5-c]quinolin-4-amines. Some of these compounds have nanomolar affinity for the A1 receptor. The structure-activity relationships (SAR) of these compounds are discussed in relation to SAR for other adenosine receptor ligands. The 1H-imidazo[4,5-c]quinolin-4-amines constitute a novel class of non-xanthine adenosine antagonists.

Selective Allosteric Enhancement of Agonist Binding and Function at Human A3 Adenosine Receptors by a Series of Imidazoquinoline Derivatives

“…The imidazoquinoline analogs were tested in competitive binding assays at human A 3 receptors, and K i values ranging from 120 nM to 101 M were observed; as for many allosteric modulators of GPCRs, an orthosteric competitive effect was also present. One of the compounds, DU124482, was suggested to be a selective A 1 receptor antagonist (van Galen et al, 1991); the present study further confirmed this selectivity by virtue of weak affinity at A 3 receptors.…”

“…These imidazoquinoline derivatives were first reported as antagonists of A 1 and A 2A receptors (van Galen et al, 1991). The imidazoquinoline analogs were tested in competitive binding assays at human A 3 receptors, and K i values ranging from 120 nM to 101 M were observed; as for many allosteric modulators of GPCRs, an orthosteric competitive effect was also present.…”

International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and Classification of Adenosine Receptors—An Update

“…van Galen et al (1991) originally introduced the imidazoquinolinamines as A 1 receptor antagonists. In addition to orthosteric binding competitive with the native ligand adenosine, the compound DU124183 was an allosteric enhancer of radioligand binding at the A 3 adenosine receptor.…”

Palladium‐Catalyzed Cross‐Coupling Reactions of Diazine N‐Oxides with Aryl Chlorides, Bromides, and Iodides

“…High-yielding arylations are possible not only with aryl bromides but also with aryl iodides (Table 2, entries 17 and 18) and even with aryl chlorides (entries [13][14][15][16]. With aryl iodides, Ag 2 CO 3 must be employed as an additive.…”

“…[14] A second direct arylation can add a second aromatic group as in the formation of 9. Alternatively, the N-oxide may be converted to chloropyrazine 10 by reaction with POCl 3 [15] and subsequently used in a wide range of palladium catalyzedcross coupling reactions. To illustrate this possibility, a Buchwald-Hartwig amination was performed, giving 11 in 70 % yield.…”