Selective A₃ Adenosine Receptor Antagonists:  Water-Soluble 3,5-Diacyl-1,2,4-trialkylpyridinium Salts and Their Oxidative Generation from Dihydropyridine Precursors

Abstract

A(3) adenosine receptor antagonists are sought for their potential antiinflammatory, antiasthmatic, and antiischemic properties. We have found that 3,5-diacyl-1,2,4-trialkyl-6-phenylpyridinium derivatives constitute a novel class of selective A(3) adenosine receptor antagonists. The structure-activity relationships of this class of antagonists, incorporating the 3-thioester, have been explored. The most potent analogue in this group was 2, 4-diethyl-1-methyl-3-(ethylsulfanylcarbonyl)-5-ethyloxycarbonyl -6-phe nylpyridinium iodide (11), which had an equilibrium inhibition constant (K(i)) value of 219 nM at human A(3) receptors (binding of [(125)I]AB-MECA (N(6)-(4-amino-3-iodobenzyl)-5'-N-methylcarbamoyladenosine)) expressed in Chinese hamster ovary (CHO) cells and >10 microM at rat brain A(1) and A(2A) receptors and at recombinant human A(2B) receptors. Compound 11 could be generated through oxidation of the corresponding 3,5-diacyl-1,2,4-trialkyl-6-phenyl-1,4-dihydropyridine, 24, with iodine or in the presence of rat brain homogenates. A 6-cyclopentyl analogue was shown to increase affinity at human A(3) receptors upon oxidation from the 1-methyl-1,4-dihydropyridine analogue, 25, to the corresponding pyridinium derivative, 23 (K(i) 695 nM), suggesting a prodrug scheme. Homologation of the N-methylpyridinium derivatives to N-ethyl and N-propyl at the 1-position caused a progressive reduction in the affinity at A(3) receptors. Modifications of the alkyl groups at the 2-, 3-, 4-, and 5-positions failed to improve potency in binding at A(3) receptors. The pyridinium antagonists are not as potent as other recently reported, selective A(3) receptor antagonists; however, they display uniquely high water solubility (43 mM for 11). Compound 11 antagonized the inhibition of adenylate cyclase elicited by IB-MECA in CHO cells expressing the human A(3) adenosine receptor, with a K(B) value of 399 nM, and did not act as an agonist, demonstrating that the pyridinium salts are pure antagonists.

A3 Adenosine Receptors as Modulators of Inflammation: From Medicinal Chemistry to Therapy

“…General SAR of pyridine derivatives revealed that structural requirements responsible for enhancement of A 3 AR affinity and selectivity did not completely reflect that of the DHP parent compounds . Among this series, were also reported fluorinated and hydroxylated pyridine derivatives and an extension of this study performed by Jacobson and co‐workers described a series of N ‐alkylpyridinium salts as water soluble A 3 AR antagonists although with lower potency than the pyridine analogues . A pyridine‐based A 3 AR antagonist PET ligand [ 18 F]FE@SUPPY was introduced …”

Probing adenosine and P2 receptors: Design of novel purines and nonpurines as selective ligands

“…A prodrug scheme for the oxidative generation of pyridinium salts which act as antagonists of the human A 3 AR from the corresponding 1-alkyldihydropyridine derivatives. Such antagonists are highly watersoluble in contrast to most other classes of A 3 AR antagonists, which are hydrophobic [Xie et al, 1999].…”

“…5) constituted a novel class of selective A 3 AR antagonists of moderate affinity [Xie et al, 1999]. The SARs of this class of antagonists, incorporating the 3-thioester, were explored.…”

A Comparison in the Use of the Crystallographic Structure of the Human A1 or the A2A Adenosine Receptors as a Template for the Construction of a Homology Model of the A3 Subtype

“…A specific subset of agonists and antagonists against hA 3 AR has been selected basing on their potency and selectivity profiles, maximizing as much as possible their chemical diversity [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48]. The selected ligands are shown in Figures 2 and 3.…”