title: A pyridoxine cyclic phosphate and its 6-azoaryl derivative selectively potentiate and antagonize activation of P2X1 receptors.
abstract: Analogues of the P2 receptor antagonists pyridoxal-5'-phosphate and the 6-azophenyl-2',4'-disulfonate derivative (PPADS), in which the phosphate group was cyclized by esterification to a CH2OH group at the 4-position, were synthesized. The cyclic pyridoxine-alpha4, 5-monophosphate, compound 2 (MRS 2219), was found to be a selective potentiator of ATP-evoked responses at rat P2X1 receptors with an EC50 value of 5.9 +/- 1.8 microM, while the corresponding 6-azophenyl-2',5'-disulfonate derivative, compound 3 (MRS 2220), was a selective antagonist. The potency of compound 3 at the recombinant P2X1 receptor (IC50 10.2 +/- 2.6 microM) was lower than PPADS (IC50 98.5 +/- 5.5 nM) or iso-PPADS (IC50 42.5 +/- 17.5 nM), although unlike PPADS its effect was reversible with washout and surmountable. Compound 3 showed weak antagonistic activity at the rat P2X3 receptor (IC50 58.3 +/- 0.1 microM), while at recombinant rat P2X2 and P2X4 receptors no enhancing or antagonistic properties were evident. Compounds 2 and 3 were found to be inactive as either agonists or antagonists at the phospholipase C-coupled P2Y1 receptor of turkey erythrocytes, at recombinant human P2Y2 and P2Y4 receptors, and at recombinant rat P2Y6 receptors. Similarly, compounds 2 and 3 did not have measurable affinity at adenosine A1, A2A, or A3 receptors. The lack of an aldehyde group in these derivatives indicates that Schiff's base formation with the P2X1 receptor is not necessarily required for recognition of pyridoxal phosphate derivatives. Thus, compounds 2 and 3 are relatively selective pharmacological probes of P2X1 receptors, filling a long-standing need in the P2 receptor field, and are also important lead compounds for future studies.
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892-0810, USA. kajacobs@helix.nih.gov
authors.forename: K A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: Y C
authors.initials: YC
authors.lastname: Kim
authors.forename: S S
authors.initials: SS
authors.lastname: Wildman
authors.forename: A
authors.initials: A
authors.lastname: Mohanram
authors.forename: T K
authors.initials: TK
authors.lastname: Harden
authors.forename: J L
authors.initials: JL
authors.lastname: Boyer
authors.forename: B F
authors.initials: BF
authors.lastname: King
authors.forename: G
authors.initials: G
authors.lastname: Burnstock
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001391:Azo Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000096:biosynthesis; D007473:Ion Channels / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000187:drug effects; D018048:Receptors, Purinergic P2 / Q000096:biosynthesis; D058469:Receptors, Purinergic P2X; D011994:Recombinant Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014421:Turkey; D014981:Xenopus
chemical_list: D001391:Azo Compounds; D007295:Inositol Phosphates; D007473:Ion Channels; C112857:MRS 2219; C112858:MRS 2220; D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D018047:Receptors, Purinergic P1; D018048:Receptors, Purinergic P2; D058469:Receptors, Purinergic P2X; D011994:Recombinant Proteins; D011732:Pyridoxal Phosphate; D000255:Adenosine Triphosphate