Synthesis and Structure−Activity Relationships of Suramin-Derived P2Y₁₁ Receptor Antagonists with Nanomolar Potency

Abstract

Selective and potent P2Y(11) receptor antagonists have yet to be developed, thus impeding an evaluation of this G protein-coupled receptor mainly expressed on immune cells. Taking suramin with moderate inhibitory potency as a template, 18 ureas with variations of the methyl groups of suramin and their precursors were functionally tested at P2Y(11), P2Y(1), and P2Y(2) receptors. Fluorine substitution of the methyl groups of suramin led to the first nanomolar P2Y(11) antagonist (8f, NF157, pK(i): 7.35). For selectivity, 8f was also tested at various P2X receptors. 8f displayed selectivity for P2Y(11) over P2Y(1) (>650-fold), P2Y(2) (>650-fold), P2X(2) (3-fold), P2X(3) (8-fold), P2X(4) (>22-fold), and P2X(7) (>67-fold) but no selectivity over P2X(1). QSAR studies confirm that residues with favored resonance and size parameters in the aromatic linker region can indeed lead to an increased potency as is the case for 8f. A symmetric structure linking two anionic clusters seems to be required for bioactivity. 8f may be helpful for studies evaluating the physiological role of P2Y(11) receptors.

Endothelial P2Y2 receptor regulates LPS-induced neutrophil transendothelial migration in vitro

“…2). Note that for the selective inhibition of P2Y 11 we used 1 μM NF157 as higher concentrations of this antagonist affect other P2Y subtypes including P2Y 2 (Ullmann et al, 2005). In agreement, 100 μM NF157 inhibited neutrophil migration by 70% (data not shown).…”

A critical look at the function of the P2Y11 receptor

“…This antagonist was tested for P2Y 11 selectivity and showed partial selectivity over P2Y 1,2 and P2X2,3,4,7 but not towards P2X1 [79]. Another more specific P2Y 11 antagonist 4,4′-(carbonylbis(imino-3,1-(4-methyl-phenylene)-carbonylimino))-bis(naphthalene-2,6-disulfonic acid) tetrasodium salt (NF340) had four times as much antagonistic potency as NF157 in a Ca 2+ -based assay and ten times the potency in a cAMP assay.…”

Development of a comprehensive set of P2 receptor pharmacological research compounds

“…The elucidation of this suramin analogue with different binding specificities highlighted the importance of the precise structural position of sulphonic acid groups within the molecule having a direct effect on its P2 receptor binding properties. The second compound was a potent, selective P2Y 11 antagonist NF 157 (15) [22]. With the exception of suramin itself, NF 157 was the only known P2Y 11 antagonist at that time.…”

“…MRS 2179 was one of the first compounds to have a high affinity and selectivity for P2Y 1 , with no significant activity at other P2Y receptor subtypes, and it has established itself as a widely used probe. As a result of another licensing agreement, Tocris were able to introduce the three closely structurally related and synthetically extremely challenging P2Y 1 -targeted compounds, namely MRS 2365 (22), MRS 2279 (23) and MRS 2500 (24) [31][32][33]. These compounds originate from the NIH Molecular Recognition Section headed by Ken Jacobson, and include the 'methanocarba' modification, a ring-constrained combination of cyclopropane and cyclopentane rings which enables retention of high affinity for P2Y 1 that is lost in other ATP analogues [31].…”