Structure-activity relationships of 8-styrylxanthines as A2-selective adenosine antagonists

Abstract

A series of substituted 8-styryl derivatives of 1,3,7-alkylxanthines was synthesized as potential A2-selective adenosine receptor antagonists, and the potency at rat brain A1- and A2-receptors was studied in radioligand binding experiments. At the xanthine 7-position, only small hydrophobic substituents were tolerated in receptor binding. 7-Methyl analogues were roughly 1 order of magnitude more selective for A2 versus A1 receptors than the corresponding 7-H analogues. 1,3-Dimethylxanthine derivatives tended to be more selective for A2-receptors than the corresponding 1,3-diallyl, diethyl, or dipropyl derivatives. Substitutions of the phenyl ring at the 3-(monosubstituted) and 3,5-(disubstituted) positions were favored. 1,3, 7-Trimethyl-8-(3-chlorostyryl)xanthine was a moderately potent (Ki vs [3H]CGS 21680 was 54 nM) and highly A2-selective (520-fold) adenosine antagonist. 1,3,7-Trimethyl-8-[(3-carboxy-1-oxopropyl)amino] styryl]xanthine was highly A2-selective (250-fold) and of enhanced water solubility (max 19 mM). 1,3-Dipropyl-7-methyl-8-(3,5-dimethoxystyryl) xanthine was a potent (Ki = 24 nM) and very A2-selective (110-fold) adenosine antagonist.

Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

“…103 Of particular importance was the discovery that substitution at C-8 with a styryl functional group yielded potent and selective A 2A antagonists. 24,46,102,103 Therefore, a large portion of the of reported A 2A antagonists are 1,3-dimethyl, 1,3-diethyl or 1,3-dipropyl substituted xanthinyl analogues bearing an (E)-8-styryl moiety modified on the phenyl ring.…”

“…106 Another xanthinyl derivative, CSC is commercially available and is used extensively as a reference A 2A antagonist in pharmacological studies. 24,25 Replacement of the styryl phenyl ring with a heterocyclic system as in the case of (E)-1,3-dipropyl-7-methyl-8-[2-(3-thienyl)ethenyl)]xanthine (DPMTX) (5) also produces a series of potent and selective A 2A antagonists. 107 Structure-activity relationship studies have shown that alkylation at N-7 of the xanthine and the trans geometry about the styryl double bond are structural features that are important for potent A 2A antagonism (Table 3).…”

“…110 The K i value for the inhibition of MAO-B by CSC is comparable to that reported for the antagonism of A 2A receptors (K i ϭ 36 -54 nM). 24,25 Structure-activity relationship studies further revealed that an electron-deficient styryl side chain was more effective in enhancing MAO-B inhibition potency and that the trans geometry about the styryl double bond is a requirement for MAO-B inhibition. 27,28 Saturation of the styryl double bond has a negative effect on inhibition potency.…”

“…22,23 (E)-8-(3-Chlorostyryl)caffeine (CSC) (1) (FIG. 1), a well known A 2A antagonist, 24,25 has been shown to be a potent, reversible inhibitor of MAO-B. 26 -28 This finding has raised the possibility of designing dual-target-directed drugs that may provide enhanced symptomatic relief and that may also slow the progression of PD by protecting against further neurodegeneration.…”

8‐(3‐Isothiocyanatostyryl)caffeine is a selective, irreversible inhibitor of striatal A2‐Adenosine receptors

“…An isothiocyanate derivative (1,3,7-trimethyl-8-(3-isothiocyanato-styryl)xanthine, ISC, 2) in the A 2 -selective, 8-styrylxanthine series of adenosine antagonists [Shimada et al, 1992;Jacobson et al, 1993] was prepared as a potential receptor affinity label. It was synthesized by reaction of the corresponding 3-amino derivative , 1, with thiophosgene ( Fig.…”