ADENOSINE RECEPTOR AGONISTS AND ANTAGONISTS

腺苷受体激动剂和拮抗剂

• 批准号: 3875853
• 负责人: J W DALY
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3875853
• 关键词: adenine analog; adenosine; adenylate cyclase; caffeine; calcium channel; chemical structure function; depression; drug design /synthesis /production; drug metabolism; drug receptors; imidazoledione; inhibitor /antagonist; ligands; pyrazolopyrimidine; radiotracer; receptor binding; stimulant /agonist; theophylline; xanthines

Adenosine regulates a wide range of physiological functions through interaction with at least two major classes of adenosine receptors. The A1 class of adenosine receptors is inhibitory to adenylate cyclase, while the A2 class is stimulatory to adenylate cyclase. Subclasses of adenosine receptors also occur. Some of these are inhibitory to calcium channels, some are stimulatory to potassium channels, some can activate guanylate cyclase, some can modulate phospholipid, while those of smooth muscle cause relaxation through a poorly defined mechanism. In the central nervous system activation of adenosine receptors cause behavioral depression, while blockade of adenosine receptors cause excitation. Antinociceptive activity of six N(6) - substituted adenosine correlated with A(1) receptor potency. Adenosine analogs relaxed carbamylcholine-contracted trachea via two receptor mechanisms, one mechanism involved a xanthine-sensitive A2 receptor and the other a xanthine-insensitive receptor. The latter was the major site of action for 2-phenylaminoadenosine and 5'-methylthioadenosine. Adenosine analogs elicited central depressant effects via both A1 and A2 receptors. Potentiative interactions between the two receptor systems appear to account for the high potency of nonselective agents, such as N-ethylcarboxamidoadenosine. A series of 7-deazapurines with substuents in the 2-, 6-, and 9-positions were synthesized. The most potent A antagonist was R-7,8-dimethyl-2-phenyl-9-(1-phenylethyl)-7-deazaadenine, which was 30-35 times more potent than its S-enantiomer. 2-p-Chlorophenyl-7, 8-dimethyl- 9-phenyl-7-deazaadenine was a potent and specific antagonist for brain A, receptors. Imidazo[4, 5-e][1-4]diazepine5, 8-diones, designed as cyclic homologs of caffeine, theophylline and other xanthines, were less active at adenosine receptors, than the corresponding xanthines, presumably because of the nonplanar ring system of the imidazodiazepindiones.

腺苷通过 与至少两个主要类别的腺苷受体相互作用。 A1 腺苷受体类是抑制腺苷酸环化酶，而 A2类是腺苷酸环化酶的刺激性。腺苷的子类 也会发生受体。其中一些是对钙通道的抑制作用， 有些是对钾通道的刺激性，有些可以激活鸟甘酸盐 循环酶，有些可以调节磷脂，而平滑肌的磷脂会导致磷脂 通过定义较差的机制放松。中央紧张 腺苷受体的系统激活会导致行为抑郁，而 腺苷受体的封锁引起激发。抗伤害感受活性 在六个N（6）中，取代的腺苷与A（1）受体效力相关。 腺苷类似物通过两个 受体机制，一种机制涉及黄嘌呤敏感的A2 受体和其他对黄嘌呤不敏感的受体。后者是 2-苯基氨基腺苷和5'-甲基硫代腺苷的主要作用部位。 腺苷类似物通过A1和A2引起中心抑制作用 受体。两个受体系统之间的增强性相互作用 似乎是非选择性剂的高效力，例如 N-乙基辅助辅助腺苷。一系列7二氮嘌呤，取代 合成了2，6和9位。最有力的对手 为R-7,8-二甲基-2-苯基-9-（1-苯基乙基）-7-二核，这是 比其S-Enantiomer高30-35倍。 2-p-氯苯基-7， 8-二甲基-9-苯基-7-二唑是一种有效且特异性的拮抗剂 对于大脑A，受体。 Imidazo [4，5-e] [1-4]地西班皮5，8二元，设计 由于咖啡因，茶碱和其他黄嘌呤的环状同源物较少 活跃于腺苷受体，而不是相应的黄嘌呤 由于咪唑唑嗪的非平面环系统。