P2 purinoceptor antagonist properties of pyridoxal-5-phosphate

Trezise, Derek J.; Bell, Noah; Khakh, Baljit S.; Michel, Anton D.; Humphrey, P. P. A.

doi:10.1016/0014-2999(94)90656-4

Cited by 40 publications

(27 citation statements)

References 17 publications

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“…PPADS was also found to inhibit the hydrolytic activity of ectoATPase, thus enhancing ATP potency at both P2X and P2Y receptors and complicating the pharmacological analysis of PPADS antagonism in assay systems [Windscheif et al, 1995a;Chen et al, 1996;Ziganshin et al, 1996]. Such complications notwithstanding, PPADS does not noticeably interact with α 1 and β 1 adrenoceptors, muscarinic (M 1-4 ), histamine (H 1 ), serotonin (5-HT 3 ) or adenosine (A 1 and A 2B ) receptors [Lambrecht et al, 1992[Lambrecht et al, , 2000Boyer et al, 1994;Trezise et al, 1994a;Ziganshin et al, 1994], and, therefore, remains a useful template to design chemical derivatives with improved potency and selectivity at P2X receptor subtypes.…”

Section: Introductionmentioning

confidence: 93%

“…The first PPADS derivative investigated for altered potency was pyridoxal-5′-phosphate (P5P), which is a derivative of pyridoxine (vitamin B 6 ) and was reported to block P2X receptors in rat vagus nerve (pK B , 5.4) and rat vas deferens (pK B , 5.3) in a competitive manner [Trezise et al, 1994a]. Pyridoxine α 4,5 -monophosphate (MRS 2219, a cyclized form of P5P) lost antagonist activity at P2X 1-4 receptors and potentiated ATP-responses at P2X 1 receptors ].…”

Section: Introductionmentioning

confidence: 99%

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Actions of a series of PPADS analogs at P2X₁ and P2X₃ receptors

Brown

Kim

et al. 2001

Drug Development Research

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[Table: see text] Seven PPADS (yridoxal-5'-hosphate 6-zophenyl 2',4'-iulfonate) analogs were investigated at Group 1 P2X receptors expressed in Xenopus oocytes. All seven analogs potently inhibited P2X (IC range, 5-32 nM) and P2X (IC range, 22-345 nM), the two Group I P2X receptor subtypes. Analogs showed greater inhibitory activity where the pyridoxal moiety of PPADS contained a 5'-phosphonate group, rather than a 5'-phosphate group. Analogs also showed greater potency where disulfonate groups were removed from, or substituted at, the azophenyl moiety. The most active analog was MRS 2257 (pyridoxal-5'-phosphonate 6-azophenyl 3',5'-bismethylenephosphonate) at P2X (IC, 5 nM) and P2X (IC, 22 nM) receptors, being 14-fold and 10-fold more potent than PPADS itself. MRS 2257 produced a nonsurmountable inhibition when tested against a range of ATP concentrations, although blockade was reversed by about 85% after 20 minutes of washout. TNP-ATP and IpI were equipotent with MRS 2257 at P2X receptors, whereas TNP-ATP was 64-fold more potent than MRS 2257 at P2X receptors. In conclusion, the PPADS template can be altered at the pyridoxal and phenyl moieties to produce P2X and P2X receptor antagonists showing higher potency and greater degree of reversibility than the parent compound at these Group I P2X receptors.

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Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Actions of a series of PPADS analogs at P2X₁ and P2X₃ receptors

Brown

Kim

et al. 2001

Drug Development Research

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“…In the present study, UTP and ATP triggered transmitter release, but acted upon separate receptors, as shown by the following: (i) The secretory response to either UTP or ATP showed homologous desensitization, but not cross-desensitization, i.e. overflow evoked by UTP was significantly reduced after preexposure to UTP, but not after pre-exposure to ATP, and vice versa; (ii) the P2 purinoceptor antagonist, suramin (Dunn & Blakeley, 1988) and pyridoxal-5'-phosphate (Trezise et al, 1994) reduced the overflow evoked by ATP, but not that evoked by UTP; (iii) Zn2" (10 ymol l-'), which enhances ATP-induced currents (Cloues et al, 1993), increased transmitter release evoked by ATP, but reduced the release evoked by UTP.…”

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confidence: 99%

UTP‐ and ATP‐triggered transmitter release from rat sympathetic neurones via separate receptors

Boehm

Huck

Illéš

1995

British J Pharmacology

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In rat cultured sympathetic neurones, UDP, UTP and ATP at micromolar concentrations triggered Ca2"-dependent and tetrodotoxin-sensitive [3H]-noradrenaline release. The overflow evoked by UTP or ATP was similar at 100 ,umol I', the concentration used in all subsequent experiments. Pre-exposure of the neurones to 100 pumol I' UTP significantly reduced ensuing secretory effects of UTP but not of ATP. Conversely, pre-exposure to ATP diminished the overflow due to ATP but not that due to UTP. In the presence of 10 pmol I`pyridoxal-5'-phosphate or 30 pmol 1' suramin, the secretory response to ATP was reduced, but the effect of UTP was unaltered. Zn2+ (10 imol I-') reduced the overflow triggered by UTP, but increased the overflow due to ATP. These results indicate the presence of separate receptors for pyrimidine nucleotides and for purine nucleotides which both trigger transmitter release.

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“…Adenosine, more accurately described as a neuromodulator, activates P 1 pu-rinoceptors [81]. Recently it has been reported that PLP can act as an antagonist of purinergic depolarizations and contractions in the rat vagus nerve and vas deferens, respectively, induced by ·,ß-methyleneATP [82]. However, when 5-HT was the depolarizing agent in the vagus, PLP had no effect.…”

Section: In Vitro Interaction Of Plp With Functional Proteinsmentioning

confidence: 96%