ADENOSINE RECEPTOR AGONISTS AND ANTAGONISTS

腺苷通过多种途径调节多种生理功能

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.