ADENOSINE-A1 ANTAGONISTS .3. STRUCTURE-ACTIVITY-RELATIONSHIPS ON AMELIORATION AGAINST SCOPOLAMINE-INDUCED OR N6-((R)-PHENYLISOPROPYL)ADENOSINE-INDUCED COGNITIVE DISTURBANCE
F. Suzuki et al., ADENOSINE-A1 ANTAGONISTS .3. STRUCTURE-ACTIVITY-RELATIONSHIPS ON AMELIORATION AGAINST SCOPOLAMINE-INDUCED OR N6-((R)-PHENYLISOPROPYL)ADENOSINE-INDUCED COGNITIVE DISTURBANCE, Journal of medicinal chemistry, 36(17), 1993, pp. 2508-2518
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.