van Muijlwijk-Koezen J E, Timmerman H, Link R, van der Goot H, Ijzerman A P
Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Department of Pharmacochemistry, Vrije Universiteit, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
J Med Chem. 1998 Oct 8;41(21):3994-4000. doi: 10.1021/jm980037i.
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.
1-取代的3-(2-吡啶基)异喹啉已被证明可形成一类新型的腺苷A3受体配体。在本研究中，对这一新先导物以及这类化合物的结构-亲和力关系进行了进一步研究。首先，确定了异喹啉环1位上的酰胺基团对腺苷A3受体亲和力的影响。事实证明，甲酰胺是异喹啉和苯环之间有用的间隔基团。N-[2-(2-吡啶基)异喹啉-4-基]苯甲酰胺(VUF8507，化合物6)对腺苷A3受体的亲和力为200 nM。其次，我们研究了用一系列单取代和双取代的N-[3-(2-吡啶基)异喹啉]苯甲酰胺取代化合物6的苯甲酰胺环的影响。通过光谱技术(红外光谱和核磁共振)在固态和溶液中测定了苯甲酰胺互变异构体的比例。在大鼠脑A1和A2A受体以及克隆的人A3受体的放射性配体结合试验中测定了亲和力。苯甲酰胺显示出比脂肪族酰胺更高的腺苷A3受体亲和力。我们提出，不同苯甲酰胺的腺苷A3受体亲和力与其以亚胺醇或酰胺形式存在有关。以亚胺醇形式存在的配体显示出相对较高的腺苷A3受体亲和力。最后，我们探讨了异喹啉环C4被氮原子取代的影响。异喹啉与相应喹唑啉的比较表明，这两种化合物显示出相似的腺苷A3受体亲和力。这些研究产生了亲和力在纳摩尔范围内的强效和选择性的人腺苷A3受体配体。亚型选择性化合物4-甲氧基-N-[2-(2-吡啶基)喹唑啉-4-基]苯甲酰胺(VUF8504，13)对人腺苷A3受体的亲和力为17.0 nM，可能成为该受体药理学特性表征或生理功能研究的有用工具。
