[3H]A-804598 ([3H]2-cyano-1-[(1S)-1-phenylethyl]-3-quinolin-5-ylguanidine) is a novel, potent, and selective antagonist radioligand for P2X7 receptors

The P2X7 receptor is not essential for development of imiquimod-induced psoriasis-like inflammation in mice

“…To further examine the potential effects of P2X7 blockade on psoriasis-like inflammation, the P2X7 antagonist A-804598 [28] was used. Similar to BBG, A-804598 near-completely abrogated ATP-induced ethidium + uptake in J774 macrophages (P < 0.0001) (Fig.…”

Preclinical Evaluation of a P2X7 Receptor–Selective Radiotracer: PET Studies in a Rat Model with Local Overexpression of the Human P2X7 Receptor and in Nonhuman Primates

“…In a recent study, 3 H-A-804598 was used to determine the ex vivo brain P2X7R occupancy of different P2X7R antagonists, indicating that this class of molecules crosses the blood-brain barrier and supporting the feasibility of in vivo visualization of P2X7R with PET in the brain (13)(14)(15). An additional hurdle, however, is the P2X7R interspecies difference reported for several molecules, giving rise to different binding affinities for mouse, rat, and human P2X7R (hP2X7R) (16)(17)(18).…”

Discovery and pharmacological evaluation of a novel series of adamantyl cyanoguanidines as P2X7 receptor antagonists

“…The 5-quinolinyl 27, which is the adamantylmethyl analogue of 3 was found to be more potent than any of the compounds tested (18 nM), with five times higher potency than 3 in both the dye uptake and IL-1β release assays ( Table 3). [23] An interesting feature of the 5-quinoline is the equivalent nitrogen positioning to that of the most potent regiomeric pyridine 35 (Figure 4). This increase in potency compared to the pyridine might be due to the rigidification of the methylene linker with the bioisosteric quinoline, resulting in a more favourable restricted conformation in the binding site.…”

“…[22] More recently, the truncated analogue 2 (A-804598) was reported with an IC 50 of 9-11 nM at the mouse, rat, and human P2X 7 Rs in a calcium flux assay, with comparable potencies also observed in IL-1β release and YO-PRO ® -1 dye uptake assays. [23] These cyanoguanidine derivatives exhibit acceptable pharmacokinetic properties that have allowed for their use in vivo, and the high potency and selectivity of 2 for the P2X 7 R over other P2X receptors has led to the use of [ 3 H]A-804598 as a high affinity radioligand in rat P2X 7 R binding studies. [23] To retain the favourable pharmacokinetic properties of the truncated cyanoguanidines reported by Abbott Laboratories, but produce enhanced potency by the inclusion of the adamantyl moiety, in this work we describe an exploratory SAR study of adamantylcyanoguanidine hybrid compounds 4 (Figure 2).…”

“…[23] These cyanoguanidine derivatives exhibit acceptable pharmacokinetic properties that have allowed for their use in vivo, and the high potency and selectivity of 2 for the P2X 7 R over other P2X receptors has led to the use of [ 3 H]A-804598 as a high affinity radioligand in rat P2X 7 R binding studies. [23] To retain the favourable pharmacokinetic properties of the truncated cyanoguanidines reported by Abbott Laboratories, but produce enhanced potency by the inclusion of the adamantyl moiety, in this work we describe an exploratory SAR study of adamantylcyanoguanidine hybrid compounds 4 (Figure 2). They incorporate adamantane (pink) as the hydrophobic portion of the molecule connected to variously substituted aryl groups (green) through the cyanoguanidine linker (red).…”