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 P2X‐purinoceptor that mediates contraction of the rabbit ear central artery by ATP, α, β‐m‐ATP. On the adenine base, substitution at the C2‐position (WRC‐0440) increased the agonist potency 2‐fold and substitution at the C8‐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 N6‐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′‐hydroxyls 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‐ATP. However, the contractile response to WRC‐0433 was not desensitized by α, β‐γ‐ATP (contractile responses to all other agonists were abolished by α‐β‐γ‐ATP pretreatment), but was blocked by the α1 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 P2X‐purinoceptor antagonists. © 1995 Wiley‐Liss, Inc.