A functionalized congener approach to adenosine receptor antagonists: amino acid conjugates of 1,3-dipropylxanthine.
A functionalized congener approach to adenosine receptor antagonists: amino acid conjugates of 1,3-dipropylxanthine.
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发表时间：
1986-02
影响因子：
3.6
通讯作者：
K. Jacobson;K. Kirk;W. Padgett;J. Daly
中科院分区：
文献类型：
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作者：
K. Jacobson;K. Kirk;W. Padgett;J. Daly
1，3-二丙基-8-苯基黄嘌呤是一种合成的茶碱类似物，是腺苷在A1和A2受体上的有效拮抗剂，它通过官能化的链与氨基酸和寡肽共价连接。研究了黄嘌呤结合物作为[~3H]N_6-环己基腺苷与大鼠大脑皮质膜A_1受体特异性结合的竞争性抑制剂和抑制2-氯腺苷通过A_2受体在豚鼠脑片上引起的环磷酸腺苷蓄积的作用。延伸链上的游离氨基通常会导致A1受体的高效价。A1受体的效力(在某些情况下延伸到亚纳摩尔范围)和选择性(高达200倍)表明，这种方法可以产生一类多功能的腺苷受体拮抗剂，其中对附着部分(“载体”)的远端修饰也可以改善药效学和药代动力学参数。与简单的、不带电荷的8-苯基黄嘌呤衍生物相比，许多更强的类似物的水溶解度提高了两个数量级。载体含有D-酪氨酸的类似物具有开发腺苷受体的碘化放射性配体的潜力。这种功能化的同类方法可能适用于其他药物和前药的开发。
1,3-Dipropyl-8-phenylxanthine, a synthetic analog of theophylline and a potent antagonist of adenosine at A1 and A2-adenosine receptors, has been attached covalently through a functionalized chain to amino acids and oligopeptides. The xanthine conjugates have been studied as competitive inhibitors of the specific binding of [3H]N6-cyclohexyladenosine to A1-receptors of rat cerebral cortical membranes and for inhibition of cyclic AMP accumulation elicited by 2-chloroadenosine in guinea pig brain slices through A2-receptors. A free amino group on the extended chain generally resulted in high potency at A1-receptors. The potency (in some cases extending into the subnanomolar range) and selectivity for A1-receptors (up to 200-fold) suggest that this approach can yield a versatile class of "functionalized congeners" of adenosine receptor antagonists in which distal modifications of the attached moiety ("carrier") can serve also to improve pharmacodynamic and pharmacokinetic parameters. The water solubility in many of the more potent analogs has been enhanced by two orders of magnitude over that of simple, uncharged 8-phenyl xanthine derivatives. Analogs in which the carrier contains D-tyrosine have potential for development of iodinated radioligands for adenosine receptors. The functionalized congener approach is potentially applicable to other drugs and for development of prodrugs.