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Background  A series of 1 H -imidazo- [4,5- c ]quinolin-4-amine derivatives, represented by LUF6000 ( N -(3,4-dichloro-phenyl)-2-cyclohexyl-1 H -imidazo [4,5- c ]quinolin-4-amine), are allosteric modulators of the human A 3  adenosine receptor (AR). Here we studied the modulation by LUF6000 of the maximum effect (E max ) of structurally diverse agonists at the A 3  AR stably expressed in CHO cells.    Results  In an assay of [ 35 S]GTPγS binding, the E max  of the A 3  AR agonist Cl-IB-MECA at the A 3  AR was lower than that of the non-selective AR agonist NECA. LUF6000 exerted an E max -enhancing effect at a concentration of 0.1 μM or higher, and was shown to increase the E max  of Cl-IB-MECA and other low-efficacy agonists to a larger extent than that of the high-efficacy agonist NECA. Interestingly, LUF6000 converted a nucleoside A 3  AR antagonist MRS542, but not a non-nucleoside antagonist MRS1220, into an agonist. LUF6000 alone did not show any effect. Mathematical modeling was performed to explain the differential effects of LUF6000 on agonists with various E max . A simple explanation for the observation that LUF6000 has a much stronger effect on Cl-IB-MECA than on NECA derived from the mathematical modeling is that NECA has relatively strong intrinsic efficacy, such that the response is already close to the maximum response. Therefore, LUF6000 cannot enhance E max  much further.    Conclusion  LUF6000 was found to be an allosteric enhancer of E max  of structurally diverse agonists at the A 3  AR, being more effective for low-E max  agonists than for high-E max  agonists. LUF6000 was demonstrated to convert an antagonist into an agonist, which represents the first example in G protein-coupled receptors. The observations from the present study are consistent with that predicted by mathematical modeling.

Flexible modulation of agonist efficacy at the human A3 adenosine receptor by the imidazoquinoline allosteric enhancer LUF6000