Structure-activity relationships of 8-cycloalkyl-1,3-dipropylxanthines as antagonists of adenosine receptors

Abstract

8-Substituted xanthines currently represent the most potent class of adenosine-receptor antagonists. A series of 8-substituted 1,3-dipropylxanthines was prepared and their potency as antagonists of A1 and A2 adenosine receptors of human platelets and rat adipocytes, respectively, were determined. No agents studied were as potent as 8-cyclopentyl-1,3-dipropylxanthine as antagonists of the A1 adenosine receptor, but 8-(2-methylcyclopropyl)-1,3-dipropylxanthine was at least 1000-fold more potent as an antagonist of A1 than of A2 adenosine receptors. While most substitutions on the 8-cycloalkyl moiety caused decreased potency to inhibit both A1 and A2 adenosine receptors, 8-[trans-4-(acetamidomethyl)cyclohexyl]-1,3-dipropylxanthine was nearly equipotent as an antagonist of the two receptors and appeared to be the most potent antagonist of A2 adenosine receptors reported to date.

Antagonism of adenosine A1 receptors in the NTS does not affect the chemoreflex in awake rats

“…These data related to the cardiovascular responses to microinjection of adenosine into the NTS are consistent with the finding of St. Lambert et al (28,29) indicating a high density of adenosine A 1 receptors in the NTS. Furthermore, the effect of DPCPX in blocking the cardiovascular responses to microinjection of adenosine into the NTS is also consistent with previous studies indicating that this antagonist has a high selectivity for adenosine A 1 receptor (14,15).…”

Xanthines with C8 chiral substituents as potent and selective adenosine A1 antagonists

“…(S)-3,7-Dihydro-8-(l-methyl-2-phenylethyl)-l,3-dipropyllff-purine-2,6-dione (5c). Compound 5c (87 mg, 82%) was prepared from 1 and (S)-2-(phenylmethyl)propanoic acid (2c) and isolated as a white solid: [«Pd +38.5°(c 0.69, CHClg); mp 141-142 °C; NMR (CDClg) 12.38 (s, 1 ), 7.22-7.09 (m, 5 ),4.13 (t, J = 7 Hz, 2 ), 4.03 (t,«7=8 Hz, 2 H), 3.38 (m, 1H), 3.23 (dd, J -13 Hz, J = 8 Hz, 1 H), 2.98 (dd, J = 13 Hz, J = 7 Hz, 1 ), 1.85-1.65 (m, 4 ), 1.41 (d, J = 7 Hz, 3 ), 0.98 (m, (S) -3,7-Dihydro-8-(l-phenylpropyl)-l,3-dipropyl-lfl'-purine-2,6-dione (5f). Compound 5f (547 mg, 28%) was prepared from 1 and (S)-2-phenylbutanoic acid (2f) and isolated as a white solid: [«PD -4.0°(c 1.07, CHClg); mp 128-131 °C; NMR (CDClg) 12.52 (ß, 1H), 7.42 (d, J = 8.6 Hz, 2 ), 7.38-7.20 (m, 3 ), 4.20-4.00 (m, 5 H), 2.38 (m, 1 ), 2.19 (m, 1 ), 1.90-1.70 (m, 4 ), 0.98 (m, 9 H); MS (70 eV, Cl, CH4) m/z 355 (M+ + 1), 383 (M+ + 29), 395 (M+ + 41).…”

Adenosine receptors: pharmacology, structure-activity relationships, and therapeutic potential

“…65 8-[trans-4-(Acetamidomethyl)cyclohexyl]l,3-dipropylxanthine (41) has surprisingly high potency at A 2 receptors, unlike other cycloalkylxanthines (K i for antagonism of adenylate cyclase activity in rat adipocytes (A 1 , 8 nM) or human platelets (A 2 , 20 nM)). 66 KFM 19 (40, (±)-8-(3-oxocyclopentyl)-l,3dipropylxanthine) is a potent A 1 -selective compound with sufficient aqueous solubility to display good bioavailability. It is currently under development as a potential cognition enhancer.…”

“…An orally active analogue, GP-1-468-3, is also under development.87 Adenosine deaminase inhibitors like deoxycoformycin (66)" may also have therapeutic potential in a manner similar to AICA riboside although the in vivo efficacy of such agents requires considerable improvement.89…”