N-6,C8-disubstituted adenosine derivatives as partial agonists for adenosine A(1) receptors?
N-6,C8-disubstituted adenosine derivatives as partial agonists for adenosine A(1) receptors?
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DOI：
10.1021/jm950267m
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发表时间：
1996-03-29
影响因子：
7.3
通讯作者：
IJzerman, AP
中科院分区：
文献类型：
--
作者：
Roelen, H;Veldman, N;IJzerman, AP
本文报道了N-6，C8-二取代腺苷衍生物的合成及生物活性评价。通过三条路线，制备了两个系列的化合物，即，N-6-环戊基腺苷衍生物3a-e和C8-（环戊基氨基）腺苷类似物3e和9a-d。本文报道了其中一种化合物N-6-乙基-8-（环戊基氨基）腺苷（9 b），（斜方晶系，空间群P2（1）2（1）2（1）（No.19），其中a = 11.039（3），B = 8.708（2），和c = 24.815（12）埃，Z = 4，R1 = 0.0974，R2（w）= 0.2455）。由于分子内氢键作用，该化合物的核糖部分呈反构象。在放射性配体结合研究中对化合物进行了体外测试，得到它们对腺苷受体Al和Az的亲和力。所有化合物出现AL选择性，在高纳摩尔，低微摩尔范围内的亲和力。在A（1）受体上，也确定了所谓的GTP移位，即，在存在和不存在1 mM GTP的情况下测量的亲和力之间的比率。所有GTP偏移（值在1.1和3.8之间）均低于CPA的GTP偏移（6.0）。这种GTP移位似乎指示体内部分激动作用，因为在清醒的血压正常大鼠中，N-6-环戊基腺苷衍生物在心率降低方面显示出比原型完全激动剂N-6-环戊基腺苷更低的内在活性。
The synthesis and biological evaluation of N-6,C8-disubstituted derivatives of adenosine as potential partial agonists for adenosine receptors is described. Via three routes, two series of compounds were prepared, viz., N-6-cyclopentyladenosine derivatives 3a-e and C8-(cyclopentylamino)adenosine analogs 3e and 9a-d, respectively. The X-ray structure determination of one of these compounds, N-6-ethyl-8-(cyclopentylamino)adenosine (9b), was carried out (orthorhombic, space group P2(1)2(1)2(1) (No. 19) with a = 11.039(3), b = 8.708(2), and c = 24.815(12) Angstrom, Z = 4, R1 = 0.0974, R2(w) = 0.2455). Due to intramolecular hydrogen bonding, the ribose moiety df this compound is in an anti conformation. The compounds were tested in vitro in radioligand binding studies, yielding their affinities for Al and Az, adenosine receptors. All compounds appeared AL selective, with affinities in the high nanomolar, low micromolar range. On A(1) receptors the so-called GTP shift was also determined, i.e., the ratio between the affinities measured in the presence and absence of 1 mM GTP. All GTP shifts (values between 1.1 and 3.8) were lower than the GTP shift for CPA(6.0). This GTP shift appeared indicative for partial agonism in vivo, since the N-6-cyclopentyladenosine derivatives showed lower intrinsic activities than the prototypic full agonist N-6-cyclopentyladenosine on the decrease in heart rate in conscious, normotensive rats.