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. 2009 Apr 9;52(7):2098-108.
doi: 10.1021/jm801659w.

Novel 2- and 4-substituted 1H-imidazo[4,5-c]quinolin-4-amine derivatives as allosteric modulators of the A3 adenosine receptor

Yoonkyung Kim  1 , Sonia de Castro, Zhan-Guo Gao, Adriaan P Ijzerman, Kenneth A Jacobson
Affiliations

Novel 2- and 4-substituted 1H-imidazo[4,5-c]quinolin-4-amine derivatives as allosteric modulators of the A3 adenosine receptor

Yoonkyung Kim et al. J Med Chem. .

Abstract

4-Arylamino and 2- cycloalkyl (including amino substitution) modifications were made in a series of 1H-imidazo[4,5-c]quinolin-4-amine derivatives as allosteric modulators of the human A(3) adenosine receptor (AR). In addition to allosteric modulation of the maximum functional efficacy (in [(35)S]GTPgammaS G protein binding assay) of the A(3)AR agonist Cl-IB-MECA (15), some analogues also weakly inhibited equilibrium radioligand binding at ARs. 4-(3,5-Dichlorophenylamino) (6) or 2-(1-adamantyl) (20) substitution produced allosteric enhancement (twice the maximal agonist efficacy), with minimal inhibition of orthosteric AR binding. 2-(4-Tetrahydropyranyl) substitution abolished allosteric enhancement but preserved inhibition of orthosteric binding. Introduction of nitrogen in the six-membered ring at the 2 position, to improve aqueous solubility and provide a derivatization site, greatly reduced the allosteric enhancement. 2-(4-(Benzoylamino)cyclohexyl) analogues 23 and 24 were weak negative A(3)AR modulators. Thus, consistent with previous findings, the allosteric and orthosteric inhibitory A(3)AR effects in imidazoquinolines are structurally separable, suggesting the possible design of additional derivatives with enhanced positive or negative allosteric A(3)AR activity and improved selectivity in comparison to inhibition of orthosteric binding.

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Figures

Chart 1
Chart 1
Structures of a series of 2-cycloalkyl imidazoquinoline derivatives previously found to be positive allosteric modulators of the human A3AR.
Scheme 1
Scheme 1
Synthesis of novel 1H-imidazo-[4,5-c]quinolin-4-amine derivatives with structural variation at the 4 position.a a Reagents: (i) m-CPBA, CHCl3/CH2Cl2/MeOH; (ii) POCl3, toluene/DMF; (iii) R-PhNH2, DMF.
Scheme 2
Scheme 2
Synthesis of novel 1H-imidazo-[4,5-c]quinolin-4-amine derivatives with structural variation at the 2 position.a a Reagents: (i) polyphosphoric acid, R1CO2H; (ii) m-CPBA, CHCl3/CH2Cl2/MeOH; (iii) POCl3, toluene/DMF; (iv) R2-PhNH2, DMF; (v) LiAlH4, THF; vi) MeNH2, EtOH; (vii) H2/Pd, MeOH.
Figure 1
Figure 1
Allosteric modulation of the human A3AR by compound 6. A) Functional assay of the human A3AR. The % stimulation of binding of [35S]GTPγS by increasing concentrations of 15 under control conditions or in the presence of 10 μM of compound 3 or 6. B) Radioligand binding studies on the human A3AR. Study of the dissociation kinetics of the agonist radioligand [125I]36 under control conditions and in the presence of 10 μM of compound 3 or 6.
Figure 2
Figure 2
Allosteric modulation of the human A3AR by compound 20 or 24. A) Functional assay of the human A3AR. The % stimulation of binding of [35S]GTPγS by increasing concentrations of 15 under control conditions or in the presence of 10 μM of compound 3 or 20. B) Radioligand binding studies on the human A3AR. Study of the dissociation kinetics of the agonist radioligand [125I]36 under control conditions and in the presence of 10 μM of compound 20 or 24.
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