Structure‐activity studies of analogs of β, γ‐methylene‐ATP at P2X‐purinoceptors in the rabbit ear central artery

Structure-activity studies using naphthylmethyl analogs of β,γ-methylene-ATP were conducted at the P 2x -purinoceptor that mediates contraction of the rabbit ear central artery by ATP, α,β-m-ATP, and β,γ-m-ATP. On the adenine base, substitution at the C 2 -position (WRC-0440) increased the agonist potency 2-fold and substitution at the C 8 -position (WRC-0431) did not change agonist potency, and both compounds had the same maximal response as β,γ-m-ATP, whereas substitution at the N 6 -position (WRC-0416) abolished activity. On the D-ribose sugar, substitution on the 2'-hydroxyl generated a partial agonist (WRC-0479), which had a maximal effect of only 39% of that of β-γ-m-ATP. Attempts to substitute the 3'-hydroxyl by naphthylmethyl failed, but substitution by p-methoxybenzyl (WRC-0617) did not change potency or the maximal response. Cyclic substitution of both the 2'- and 3'-hydroxyls by naphthylmethylidine (WRC-0498) had no effect on the agonist potency or the maximal response relative to β-γ-m-ATP. On the β,γ-methylenetriphosphonate chain, substitution on the methylene linkage by naphthylmethyl (WRC-0433) had no effect on agonist potency, but the maximal response increased to 122% that of β,γ-m-ATP. However, the contractile response to WRC-0433 was not desensitized by α,β-m-ATP (contractile responses to all other agonists were abolished by α-β-m-ATP pretreatment), but was blocked by the α 1 antagonist prazosin (10 -6 M). WRC-0433 appears to act at a prejunctional site that mediates ATP-induced release of norepinephrine. Purine nucleotides with substituents at the 2'-position of the ribose sugar could provide a lead to the generation of P 2x -purinoceptor antagonists.