ADENOSINE-A1 ANTAGONISTS .3. STRUCTURE-ACTIVITY-RELATIONSHIPS ON AMELIORATION AGAINST SCOPOLAMINE-INDUCED OR N6-((R)-PHENYLISOPROPYL)ADENOSINE-INDUCED COGNITIVE DISTURBANCE

The effects of a variety of adenosine A1 and A2 antagonists on N6-((R) -phenylisopropyl)adenosine (R-PIA)- and scopolamine-induced amnesias w ere investigated in rodents in order to clarify the role of adenosine receptors in learning and memory. Some of the selective adenosine A1 a ntagonists exhibited antiamnesic activities at several doses where the y did not induce an increase of spontaneous locomotion. These results suggest that the blockade of A1 receptors is more important than that of A2 receptors in learning and memory. Detailed studies of structure- activity relationships of adenosine A1 antagonists in two amnesia mode ls demonstrated that there were three types of adenosine A1 antagonist s: (A) Compounds 3-5 (8-substituted 1,3-dipropylxanthines) ameliorated the shortened latency in both models. (B) Compounds 7-11 (8-substitut ed 1,3-dialkylxanthines) and 19-21 (imidazo[2,1-i]purin-5(4H)-one deri vatives) ameliorated the shortened latency in the (R)-PIA-induced amne sia model but not in the scopolamine-induced amnesia model. (C) Compou nds 14-16 ameliorated the shortened latency in the scopolamine model b ut not in the (R)-PIA model. Aminophenethyl-substituted compounds C di d not exhibit adenosine A1 antagonism in vivo presumably due to rapid metabolism. The dramatic change in the activities of A and B could not be explained by their simple pharmacokinetic differences because both types of compounds showed clear blockade of central adenosine A1 rece ptors in the (R)-PIA model. 8-(3-Dicyclopropylmethyl)-1,3-dipropylxant hine (5) (KF15372) was chosen for further studies and is currently und er preclinical development as a cognition enhancer.