8-(3-chlorostyryl)caffeine and 3-7-dimethyl-1-propargylxanthine

The present experiments tested the hypothesis that adenosine A2 receptors are involved in central reward function. Adenosine receptor agonists or antagonists were administered to animals that had been trained to self-stimulate in a rate-free brain stimulation reward (BSR) task that provides current thresholds as a measure of reward. The adenosine A(2A) receptor-selective agonists 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido adenosine hydrochloride (CGS 21680) (0.1-1.0 mg/kg) and 2-[(2-aminoethylamino)carbonylethyl phenylethylamino]-5'-N-ethylcarboxamido adenosine (APEC) (0.003-0.03 mg/kg) elevated reward thresholds without increasing response latencies, a measure of performance. Specifically, CGS 21680 had no effect on response latency, whereas APEC shortened latencies. Bilateral infusion of CGS 21680 (3, 10, and 30 ng/side), directly into the nucleus accumbens, elevated thresholds but shortened latencies. The highly selective A(2A) antagonist 8-(3-chlorostyryl)caffeine (0.01-10.0 mg/kg) and the A2-preferring antagonist 3,7-dimethyl-1-propargylxanthine (DMPX) (0.3-10.0 mg/kg) did not alter thresholds or latencies, but DMPX (1.0, 10.0 mg/kg) blocked the threshold-elevating effect of APEC (0.03 mg/kg). In another study, repeated administration of cocaine (eight cocaine injections of 15 mg/kg, i.p., administered over 9 hr) produced elevations in thresholds at 4, 8, and 12 hr after cocaine. DMPX (3 and 10 mg/kg), administered before both the 8 and 12 hr post-cocaine self-stimulation tests, reversed the threshold elevation produced by cocaine withdrawal. These results indicate that stimulating adenosine A(2A) receptors diminishes BSR without producing performance deficits, whereas blocking adenosine receptors reverses the reward impairment produced by cocaine withdrawal or by an A(2A) agonist. These findings indicate that adenosine, via A(2A) receptors, may inhibit central reward processes, particularly during the neuroadaptations associated with chronic drug-induced neuronal activation.

Topics: Adenosine; Animals; Brain; Caffeine; Cocaine; Differential Threshold; Dopamine Uptake Inhibitors; Drug Interactions; Electric Stimulation; Male; Phenethylamines; Purinergic P1 Receptor Agonists; Purinergic P1 Receptor Antagonists; Rats; Rats, Wistar; Reaction Time; Receptors, Purinergic P1; Reference Values; Reward; Substance Withdrawal Syndrome; Theobromine

A series of 8-substituted derivatives of 3,7-dimethyl-1-propargylxanthine (DMPX) was synthesized and investigated as A2A adenosine receptor antagonists. Different synthetic strategies for the preparation of DMPX derivatives and analogues were explored. A recently developed synthetic procedure starting from 3-propargyl-5,6-diaminouracil proved to be the method of choice for the preparation of this type of xanthine derivatives. The novel compounds were investigated in radioligand binding studies at the high-affinity adenosine receptor subtypes A1 and A2A and compared with standard A2A adenosine receptor antagonists. Structure-activity relationships were analyzed in detail. 8-Styryl-substituted DMPX derivatives were identified that exhibit high affinity and selectivity for A2A adenosine receptors, including 8-(m-chlorostyryl)-DMPX (CS-DMPX, Ki A2A = 13 nM, 100-fold selective), 8-(m-bromostyryl)-DMPX (BS-DMPX, Ki A2A = 8 nM, 146-fold selective), and 8-(3,4-dimethoxystyryl)-DMPX (Ki A2A = 15 nM, 167-fold selective). These and other novel compounds are superior to the standard A2A adenosine receptor antagonists KF17837 (4) and CSC (5) with respect to A2A affinity and/or selectivity.

Topics: Adenosine; Animals; Binding, Competitive; Brain; Caffeine; Molecular Structure; Phenethylamines; Protein Binding; Purinergic P1 Receptor Antagonists; Rats; Receptors, Purinergic P1; Structure-Activity Relationship; Theobromine; Xanthines

Adenosine antagonists potentiate dopamine-mediated behaviours. A2a adenosine and D2 dopamine receptors are abundantly co-expressed within the striatopallidal subset of striatal neurons, suggesting that this is the site of interaction between A2a and D2 receptors. We show that the D2-dependent induction of the immediate early gene c-Fos occurs in striatopallidal neurons 3 h following injection of reserpine (10 mg/kg). We used this paradigm to test whether adenosine antagonists modulate D2-dependent activation of striatopallidal neurons. The non-selective A1-A2 adenosine antagonists theophylline (25 mg/kg) or 3,7-dimethyl-1-propargylxanthine (25 mg/kg) potentiated the effect of a submaximal dose of the D2 dopamine agonist quinpirole (0.05 mg/kg) to prevent the induction of striatal c-Fos following reserpine. Co-administration of the A2a receptor antagonist 8-(3-chlorostyryl) caffeine (5 mg/kg) with quinpirole (0.05 mg/kg) also attenuated striatal c-Fos induction following reserpine to a greater extent than 0.05 mg/kg quinpirole alone. When administered prior to reserpine, theophylline (25 mg/kg) or 3,7-dimethyl-1-propargylxanthine (25 mg/kg) partially attenuate the induction of striatal c-fos. These results demonstrate that systemic administration of adenosine antagonists enhance D2 dopamine receptor-dependent regulation of c-Fos in the striatopallidal pathway. These results support a functional interaction between A2a adenosine and D2 dopamine receptors in striatopallidal neurons.

Topics: Adenosine; Adrenergic Uptake Inhibitors; Animals; Caffeine; Dopamine Agonists; Ergolines; Genes, fos; Globus Pallidus; Immunohistochemistry; Male; Neostriatum; Neural Pathways; Phosphodiesterase Inhibitors; Quinpirole; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Reserpine; Theobromine; Theophylline