Improving Potency, Selectivity, and Water Solubility of Adenosine A₁ Receptor Antagonists: Xanthines Modified at Position 3 and Related Pyrimido[1,2,3‐cd]purinediones

Abstract

The structure-activity relationships of xanthine derivatives related to the adenosine A(1) receptor antagonists 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and 1,3-dipropyl-8-(3-noradamantyl)xanthine (KW3902) were investigated by focusing on variations of the 3-substituent. Aromatic residues were well tolerated by the A(1) receptor in that position. A moderate effect of stereochemistry was found for the 3-(1-phenylethyl)-substituted analogue of DPCPX (S>R) at A(1) and A(3) receptors, whereas the opposite stereoselectivity was observed at the A(2) receptor subtypes. A 3-hydroxypropyl substituent was found to be optimal for high A(1) affinity and selectivity. The most potent compound of the present series was 1-butyl-3-(3-hydroxypropyl)-8-(3-noradamantyl)xanthine (10 c), which exhibits a K(i) value of 0.124 nM at rat, and 0.7 nM at human adenosine A(1) receptors, combined with high selectivity (>>200-fold) versus the other receptor subtypes. The similarly potent 8-cyclopentyl-3-(3-hydroxypropyl)-1-propylxanthine was converted into a water-soluble phosphate prodrug, which may become a useful pharmacological tool for in vivo studies. 8-Alkyl-2-(3-noradamantyl)pyrimido[1,2,3-cd]purine-8,10-diones, which can be envisaged as xanthine analogues with a fixed 3-propyl substituent, were identified as a new class of potent, selective adenosine A(1) receptor antagonists. For example, compound 14 (8-butyl-substituted) exhibits a K(i) value of 13.8 nM at human A(1) receptors. A selection of the most potent compounds was investigated in [(35)S]GTPgammaS binding assays and showed inverse agonistic activity. Their efficacy was generally lower than that of the full inverse agonist DPCPX, and depended on subtle structural changes. Some of the new compounds belong to the most potent and selective A(1) antagonists described to date.

Ligand-Independent Adenosine A2B Receptor Constitutive Activity as a Promoter of Prostate Cancer Cell Proliferation

“…Fig. 1) that was similar to published values (Weyler et al, 2006). Importantly, the A 2B AR was not grossly overexpressed, with a B max value of 3.13 6 0.61 pmol mg protein…”

Perisynaptic Glia Discriminate Patterns of Motor Nerve Activity and Influence Plasticity at the Neuromuscular Junction

“…Hence, one would predict that blocking A 1 receptors would alter PSC-mediated depression, whereas blocking A 2A receptors would alter PSC-mediated potentiation. Consistent with this possibility, bath application of an A 1 receptor agonist (CPA, 30 nm) (O'Neill et al, 2007;Serpa et al, 2009) Consistent with the known role of A 1 receptors at the neuromuscular synapse (Redman and Silinsky, 1994), addition of the A 1 adenosine receptor antagonist PSB-36 (5 nM) (Weyler et al, 2006) did not affect base line synaptic transmission but when applied before photolysis-mediated activation of PSCs resulted in a post-photolysis potentiation of PSP amplitude rather than a post-tetanic depression (105.8 Ϯ 1.3%, n ϭ 8; p ϭ 0.002, twotailed t test) (Fig. 7A).…”

Activation of Adenosine1 Receptors Induces Antidepressant-Like, Anti-Impulsive Effects on Differential Reinforcement of Low-Rate 72-s Behavior in Rats

“…The known pharmacological selectivity of both CHA and DPCPX for adenosine A 1 receptors indicates that the effects of these drugs are mediated via activation and blockade of adenosine A 1 receptors. Although CHA is only modestly selective for rat adenosine A 1 compared with rat adenosine A 3 receptors (Ͼ200-fold), this agonist is nearly 500-fold and more than 10,000-fold selective for rat A 2A and human A 2B receptors (Bruns, 1980;Daly et al, 1993;van Galen et al, 1994) Although DPCPX is only modestly selective for adenosine A 1 compared with A 2B receptors (ϳ400-fold), this antagonist is nearly 300-to 1000-fold and 10,000-fold selective compared with rodent A 2A and A 3 receptors, respectively (Bruns, 1980;Auchampach et al, 1997;Weyler et al, 2006). Thus, the potent antagonism exerted by DPCPX against CHA is mediated by their most potent shared site of action, adenosine A 1 receptors.…”