A2B Adenosine Receptor Agonists: Synthesis and Biological Evaluation of 2‐Phenylhydroxypropynyl Adenosine and NECA Derivatives
A2B Adenosine Receptor Agonists: Synthesis and Biological Evaluation of 2‐Phenylhydroxypropynyl Adenosine and NECA Derivatives
复制标题
A2B 腺苷受体激动剂：2-苯基羟基丙炔基腺苷和 NECA 衍生物的合成和生物学评价
DOI：
10.1081/ncn-120028340
复制
发表时间：
2004
期刊：
影响因子：
--
通讯作者：
R. Hill
中科院分区：
文献类型：
--
作者：
M. Deninno;H. Masamune;L. Chenard;K. Dirico;C. Eller;J. Etienne;Jeanene E. Tickner;S. Kennedy;D. Knight;J. Kong;J. Oleynek;W. R. Tracey;R. Hill
在寻找难以捉摸的A2 B腺苷受体亚型的激动剂时，2-苯羟丙炔基-5 ′-N-甲基甲酰氨基腺苷（PHPMECA，14），2-苯羟丙炔基-5 ′-N-丙基甲酰氨基腺苷（PHPPECA，15），和N-6-乙基-2-苯基羟基丙炔基-5 ′-N-乙基甲酰氨基腺苷（19）的合成是基于在腺苷衍生物的2-位引入炔基链导致与NECA相比相当好的A2 B效力[分别参见N-6-乙基-2-苯基羟基丙炔基腺苷（5）EC 50 = 1，700 nM和2-苯基羟基丙炔基-5 ′-N-乙基甲酰氨基腺苷（PHPNECA，8）EC 50 = 1，100 nM]。放射性配体结合研究和腺苷酸环化酶测定，最近克隆的人A1，A2 A，A2 B和A3腺苷受体进行，表明这些修改产生的效力降低A2 B受体，以及在其他受体亚型的亲和力普遍降低。另一方面，在相同化合物中同时存在N 6-位乙基取代基和4′-乙基甲酰胺基，导致（R，S）-N6-乙基-2-苯基羟基丙炔基-5 ′-N-乙基甲酰胺腺苷和（S）-N6-乙基-2-苯基羟基丙炔基-5 ′-N-乙基甲酰胺腺苷，其在A2 B亚型中未显示预期的效力增加。因此，EC 50 A2 B = 220 nM的（S）-2-苯基羟基丙炔基-5 ′-N-乙基甲酰氨基腺苷[（S）-PHPNECA]仍然是迄今为止报道的A2 B受体最有效的激动剂。[2]为了荣誉和庆祝勒罗伊教授B的70岁生日。汤森。
In the search for agonists for the elusive A2B adenosine receptor subtypes, 2‐phenylhydroxypropynyl‐5′‐N‐methylcarboxamido adenosine (PHPMECA, 14), 2‐phenylhydroxypropynyl‐5′‐N‐propylcarboxamido adenosine (PHPPECA, 15), and N 6‐ethyl‐2‐phenylhydroxypropynyl‐5′‐N‐ethylcarboxamidoadenosine (19) were synthesized on the basis that introduction of alkynyl chains in 2‐position of adenosine derivatives resulted in reasonably good A2B potency compared to NECA [see N 6‐ethyl‐2‐phenylhydroxypropynyl adenosine (5) EC50 = 1,700 nM and 2‐phenylhydroxypropynyl‐5′‐N‐ethylcarboxamido adenosine (PHPNECA, 8) EC50 = 1,100 nM, respectively]. Radioligand binding studies and adenylyl cyclase assays, performed with recently cloned human A1, A2A, A2B, and A3 adenosine receptors, showed that these modifications produced a decrease in potency at A2B receptor, as well as a general reduction in affinity at the other receptor subtypes. On the other hand, the contemporary presence of an ethyl substituent in N 6‐position and of a 4′‐ethylcarboxamido group in the same compounds led to (R,S)‐N6‐ethyl‐2‐phenylhydroxypropynyl‐5′‐N‐ethylcarboxamidoadenosine and (S)‐N6‐ethyl‐2‐phenylhydroxypropynyl‐5′‐N‐ethylcarboxamidoadenosine, which did not show the expected increase in potency at A2B subtype. Hence, (S)‐2‐phenylhydroxypropynyl‐5′‐N‐ethylcarboxamidoadenosine [(S)‐PHPNECA] with EC50 A2B = 220 nM remains the most potent agonist at A2B receptor reported so far. †In honor and celebration of the 70th birthday of Professor Leroy B. Townsend.