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Use of Active and Inactive Stabilised Versions of the a 2A Receptor to Predict Compound Efficacy in Vitro

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Use of Active and Inactive Stabilised Versions of the a 2A Receptor to Predict Compound Efficacy in Vitro Proceedings of the British Pharmacological Society at http://www.pA2online.org/abstracts/Vol10Issue1abst046P.pdf Use of active and inactive stabilised versions of the A 2A receptor to predict compound efficacy in vitro Kirstie.A Bennett 1, Benjamin Tehan 1, Guillaume Lebon 2, Christopher.G Tate 2, Christopher.J Langmead 1. 1Heptares Therapeutics Ltd, Biopark, Broadwater Rd, Welwyn Garden City, AL7 3AX, UK, 2MRC laboratory of Molecular Biology, Hills Road, Cambridge, CB2 0QH, UK One of the simplest models used to describe receptor activation is the two-state model, receptors exist in inactive (R) or active (R*) conformations, with the R* able to form and signal spontaneously in the absence of agonist (‘constitutive activity’). Agonists bind with higher affinity to the R* state, inverse agonists to the R state, whilst neutral antagonists bind with similar affinity to R and R*. Using StaR technology the A 2A receptor has previously been constrained into both R and R* states and the crystal structures solved (Robertson et al., 2011; Dore et al., 2011; Lebon et al, 2011a). Here we investigate the pharmacology of the A 2A StaRs and show that, by measuring changes in the affinity of a panel of compounds at R and R*, it is possible to predict how a compound acts in vitro and feedback this information to aid model generation for the A 2A receptor. The affinity of a panel of A 2A compounds (NECA, ZM241385, XAC, istradefylline, SCH58261, preladenant, caffeine and theophylline) were tested at both A 2A active state StaRs (GL0, GL23, GL26 and GL31) and inactive state StaR (StaR2) using [ 3H]NECA or [ 3H]ZM241385 binding assays (for methods see Lebon et al., 2011, Dore et al., 2011). To measure functional responses a CisBio cAMP assay was used to measure G αs activation of A 2A receptor in T-REx CHO cell lines after receptor expression was induced by addition of 3 ng/mL doxycycline for 16 h (for methods see Dore et al., 2011). As predicted by the two state model, NECA, which significantly loses affinity at the inactive state StaR (R) (p<0.01 compared to native receptor) but retains high affinity at the active state StaRs (R*) acts as an agonist in the cAMP assay. Preladenant, SCH58261, XAC and ZM241385 significantly lose affinity at R* (p<0.5-p<0.001 compared to native receptor) but not R and are shown to act as full inverse agonists of the A 2A , reducing basal cAMP levels down to those seen in the absence of receptor expression. Interestingly the affinities of caffeine, theophylline and istradefylline were found to be unaltered at both active and inactive StaRs compared to native receptor, and when tested in the cAMP assay, these compounds were revealed to act as partial inverse agonists i.e. they failed to fully reverse the constitutive activity of the A 2A receptor. By comparing the NECA-bound active state structure (2YDV) to the inactive state structures (ZM241385-bound; 3PWH and XAC-bound; 3REY) it can be seen agonist binding to the A 2A receptor results in a significant change in the shape of the binding site causing a contraction in the extracellular end of the receptor which reduces the size of the binding pocket. ZM241385 and XAC cannot fully fit into the agonist binding pocket defined in 2YDV. In contrast, the fragment-sized molecule caffeine can bind deep within the A 2A receptor and fully fits into the binding pocket defined in 2YDV explaining why caffeine can bind with equal affinity to R and R*. Although istradefylline is much larger in size than caffeine, the results of this study and biophysical mapping studies (Zhukov et al., 2011) suggest that istradefylline binds in a similar location to caffeine with the molecule extending towards the extracellular surface of the receptor, allowing istradefylline to fully fit within binding sites defined in both active and inactive state receptor structures. This study highlights the power of isolated, stabilised GPCR conformations (StaRs) in elucidating the molecular basis of ligand pharmacology through a combination of structural and in vitro studies, and consequently the potential for precise design of drugs with desired degrees of agonism. References Doré AS, Robertson N, Errey JC, Ng I, Hollenstein K, Tehan B et al (2011) Structure of the Adenosine Receptor A(2A) Receptor in Complex with ZM241385 and the Xanthines XAC and Caffeine. Structure. 7;19(9)1283-93 Lebon G, Warne T, Edwards PC, Bennett K, Langmead CJ, Leslie AG et al (2011a) Agonist-bound adenosine A2A receptor structures reveal common features of GPCR activation. Nature 18; 474 (7352)521-5 Robertson N, Jazayeri A, Errey J, Baig A, Hurrell E, Zhukov A, Langmead CJ, Weir M, Marshall FH. The properties of thermostabilised G protein-coupled receptors (StaRs) and their use in drug discovery. Neuropharmacology. 2011 Jan;60(1):36-44. Epub 2010 Jul 17. Zhukov A, Andrews SP, Errey JC, Robertson N, Tehan B, Mason JS, Marshall FH, Weir M, Congreve M. Biophysical mapping of the adenosine A2A receptor. J Med Chem. 2011 Jul 14;54(13):4312-23 .
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