A Novel Class of Adenosine A₃ Receptor Ligands. 1. 3-(2-Pyridinyl)isoquinoline Derivatives

Abstract

A series of 3-(2-pyridinyl)isoquinoline derivatives was synthesized as potential antagonists for the human adenosine A3 receptor by substitution of the 1-position. The compounds were obtained by various synthetic routes from 1-amino-3-(2-pyridinyl)isoquinoline. The affinity was determined in radioligand binding assays for rat brain A1 and A2A receptors and for the cloned human A3 receptor. A structure-activity relationship analysis indicated that a phenyl group when coupled by a spacer allowing conjugation on position 1 of the isoquinoline ring increased the adenosine A3 receptor affinity. In contrast, such a phenyl group directly bound to position 1 of the isoquinoline ring decreased affinity. Since the combination of a phenyl group together with a spacer raised adenosine A3 receptor affinity, various spacers were investigated. VUF8501 (N-[3-(2-pyridinyl)isoquinolin-1-yl]benzamidine (15) showed an affinity at the human adenosine A3 receptor of 740 nM. Substituent effects on the phenyl group were investigated by in vitro evaluation of a series of substituted benzamidines. Electron-donating groups at the para position of the benzamidine ring increased adenosine A3 receptor affinity. These investigations led to VUF8505 (4-methoxy-N-[3-(2-pyridinyl)isoquinolin-1-yl]benzamidine(22)), which is a moderately potent and selective ligand for the human adenosine A3 receptor with an affinity of 310 nM in our test system having negligible affinity for rat A1 and A2A receptors.

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

“…nists of this subtype (van Muijlwijk-Koezen et al, 1998). In binding assay screens of diverse ligands designed to detect enhancement, as well as inhibition, members of the pyridinyl isoquinoline class were found to exhibit allosteric as well as orthosteric properties in interaction with the receptor (Fig.…”

Synthesis and Biological Activities of 4-Phenyl-5-pyridyl-1,3-thiazole Derivatives as Selective Adenosine A3 Antagonists

“…As human adenosine A 3 receptor (hA 3 AR) antagonists, many potent and selective antagonists, such as xanthine derivatives, 11) 1,4-dihydropyridines, [12][13][14][15] triazoloquinazolines, 16,17) flavonoids, 18) triazolonaphthyridines, 19) thiazolopyrimidines, 19,20) isoquinolines, 21,22) quinazolines, 21) pyrazolotriazolopyrimidines, [23][24][25] thiazoles and thiadiazoles, 26) and triazolopurines 27,28) have been reported as new hA 3 AR antagonists. Although these antagonists showed strong hA 3 AR antagonistic activity and good selectivity against other adenosine receptor subtypes, they were found to be weak or ineffective against rat A 3 AR (rA 3 AR), 1,11,12,15,28,29) and could therefore not be evaluated in rat in vivo models.…”

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.…”

“…22 Os estudos de biososterismo realizados permitiram concluir que o incremento de átomos de nitrogênio no heterociclo não originava uma melhoria significativa da interação com o receptor A 3 . Destes estudos salienta-se o composto 45 (Figura 5B) que possui uma afinidade para o receptor na ordem de nanomolar 50 …”