A Novel Class of Adenosine A₃ Receptor Ligands. 2. Structure Affinity Profile of a Series of Isoquinoline and Quinazoline Compounds

Abstract

1-Substituted 3-(2-pyridinyl)isoquinolines have been shown to form a novel class of adenosine A3 receptor ligands. In the present study further investigations of this new lead and the structure affinity relationships of this class of compounds are described. First, the influence of an amide group at position 1 of the isoquinoline ring on the adenosine A3 receptor affinity was determined. A carboxamide proved to be a useful spacer between the isoquinoline and a phenyl ring. N-[2-(2-pyridinyl)isoquinolin-4-yl]benzamide (VUF8507, compound 6) had an affinity of 200 nM at the adenosine A3 receptor. Second, we investigated the effects of substitution of the benzamide ring of 6 with a series of mono- and disubstituted N-[3-(2-pyridinyl)isoquinoline]benzamides. The ratio of the tautomers of the benzamides was determined in the solid state and in solution by spectroscopic techniques (IR and NMR). Affinities were determined in radioligand binding assays at rat brain A1 and A2A receptors and at cloned human A3 receptor. The benzamides showed higher adenosine A3 receptor affinity than aliphatic amides. We propose that the adenosine A3 receptor affinity of the different benzamides is related to their presence in either the iminol or amide form. Ligands present in the iminol form showed relatively high adenosine A3 receptor affinity. Finally, we explored the influence of replacement of C4 of the isoquinoline ring by a nitrogen atom. Comparison of isoquinolines with the corresponding quinazolines revealed that both compounds showed similar adenosine A3 receptor affinity. These investigations led to potent and selective human adenosine A3 receptor ligands with affinities in the nanomolar range. The subtype-selective compound 4-methoxy-N-[2-(2-pyridinyl)quinazolin-4-yl]benzamide (VUF8504, 13) with an affinity of 17.0 nM at the human adenosine A3 receptor might become a useful tool in the pharmacological characterization or the investigation of the physiological function of this receptor.

Quinazolines as adenosine receptor antagonists: SAR and selectivity for A2B receptors

“…These derivatives distantly resemble isoquinolines reported as A 3 AR antagonists. 19 Most of the structural variation occurred at the 2-position, with guanidino and substituted guanidino groups. Simple functional group substitution of the phenyl ring was included.…”

Receptores A3 da adenosina: uma nova abordagem terapêutica no câncer

“…[50][51][52] A substituição do espaçador amidina por um grupo amida (compostos 42-43, Figuras 5B e C) levou à obtenção de derivados com propriedades semelhantes aos descritos anteriormente, no entanto, a introdução de um grupo doador de elétrons (-OCH 3 ) na posição para do grupo fenila (composto 43, Figura 5B) levou a um incremento de atividade, quer de afinidade quer de seletividade, para o receptor A 3 . A presença do grupo benzamido faz com que estes compostos possam existir sob duas formas tautoméricas -a forma amida ou a forma iminol -tendo sido verificado que a presença de um grupo doador de elétrons no grupo fenila existente no espaçador é capaz de determinar a forma tautomérica predominante do ligante.…”

Functionalized Congeners of 1,4-Dihydropyridines as Antagonist Molecular Probes for A3 Adenosine Receptors

“…Within the series of DHP derivatives, affinity and selectivity for the human A 3 receptor were further enhanced in the trisubstituted analogue MRS 1191, 3-ethyl 5-benzyl 2-methyl-6-phenyl-4-phenylethynyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (Table 1, 1b) (12). Other A 3 selective antagonists that have been recently reported include a flavonoid derivative (MRS 1067, 1c) (11), a triazolonaphthyridine (L-249313, 1d) (13), a pyridine (MRS 1523, 1e) (14), and a pyridyl isoquinoline (VUF 8504, 1f) (15).…”

“…A 3 adenosine receptor antagonists, although only recently introduced (11)(12)(13)(14)(15)(16), were previously hypothesized to act as potential antiasthmatic (17), antiinflammatory (17), or cerebroprotective agents (18). The most promising leads for A 3 receptor antagonists have appeared recently among chemically diverse nonxanthine heterocycles ( Figure 1).…”