In search of selective P2 receptor ligands: interaction of dihydropyridine derivatives at recombinant rat P2X2 receptors

Abstract

Abstract1,4-Dihydropyridines are regarded as privileged structures for drug design, i.e. they tend to bind to a wide variety of receptor sites. We have shown that upon appropriate manipulation of the substituent groups on a 1,4-dihydropyridine template, high affinity and selectivity for the A 3 subtype of adenosine receptors ('P1 receptors') may be attained. In the present study we have begun to extend this approach to P2 receptors which are activated by ATP and other nucleotides. Nicardipine, a representative dihydropyridine, used otherwise as an L-type calcium channel blocker, was shown to be an antagonist at recombinant rat P2X 2 (IC 50 = 25 μM) and P2X 4 (IC 50 2 20 μM) receptors expressed in Xenopus oocytes. Thus, this class of compounds represents a suitable lead for enhancement of affinity through chemical synthesis. In an attempt to modify the 1,4-dihydropyridine structure with a predicted P2 receptor recognition moiety, we have replaced one of the ester groups with a negatively charged phosphonate group. Several 4-phenyl-5-phosphonato-1,4-dihydropyridine derivatives, MRS 2154 (2,6-dimethyl), MRS 2155 (6-methyl-2-phenyl), and MRS 2156 (2-methyl-6-phenyl), were synthesized through three component condensation reactions. These derivatives were not pure antagonists of the effects of ATP at P2X 2 receptors, rather were either inactive (MRS 2156) or potentiated the effects of ATP in a concentration-dependent manner (MRS 2154 in the 0.3-10 μM range and MRS 2155 at >1 μM). Antagonism of the effects of ATP at P2X 2 receptor superimposed on the potentiation was also observed at >10 μM (MRS 2154) or 0.3-1 μM (MRS 2155). Thus, while a conventional dihydropyridine, nicardipine, was found to antagonize rat P2X 2 receptors ninefold more potently than P2X 4 receptors, the effects of novel, anionic 5-phosphonate analogues at the receptor were more complex.

Privileged Structures - Dream or Reality: Preferential Organization of Azanaphthalene Scaffold

“…Nifedipine [76,90,91] Nicardipine [92] Nilvadipine [83,93] Felodipine [94] ( sulfonamide [67,75], spiroindanyl piperidine [75], 1,4-dihydropyridine [76], 2,6-dichloro-9-thiabicyclo[3.3.1]nonane [77], benzopyran [78,79], pyridazines [80], indoles and quinolines [81,82].…”

Dihydropyridines Potentiate ATP-Induced Currents Mediated by the Full-Length Human P2X5 Receptor

“…Specific blockers of P2X5 receptors are unknown to date [ 1 ]. However, it was reported recently that α,β-methylene ATP-induced contractions were inhibited by nifedipine in rat vascular smooth muscle cells [ 40 ] and that nicardipine reduced the current induced at recombinant rat P2X2 and P2X4 receptors expressed in Xenopus oocytes [ 28 ]. Therefore, we investigated the effect of several dihydropyridines on hP2X5 FL .…”

“…Thus, it is conceivable to repurpose this scaffold for diverse targets. In the case of purinergic signaling pathways, various DHPs have been found to inhibit P2X2 receptors, adenosine receptors, and the equilibrative nucleoside transporter (ENT1) [ 28 , 29 , 30 ].…”

Characterizing the Presence and Sensitivity of the P2X7 Receptor in Different Compartments of the Gut

“…The macrophages and lymphocytes from the lymph nodes are more susceptible to ATPe compared with the macrophages and lymphocytes from other sources. The literature reports that the EC 50 for the agonist (ATP) of the P2X7 receptor is approximately 780 µ M in macrophages [28]. Several hypotheses could explain this increase in the sensitivity to ATPe.…”