Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1993 Feb;108(2):490–496. doi: 10.1111/j.1476-5381.1993.tb12830.x

Quantitative analysis of the agonist and antagonist actions of some ATP analogues at P2X-purinoceptors in the rabbit ear artery.

P Leff 1, B E Wood 1, S E O'Connor 1, K McKechnie 1
PMCID: PMC1907965  PMID: 8448598

Abstract

1. The agonist and antagonist effects of a series of beta, gamma-methylene dihalo- and 2-methylthio-substituted analogues of ATP at P2x-purinoceptors have been analysed on the rabbit isolated ear artery preparation. Cumulative and sequential dosing experimental protocols were employed in the construction of agonist concentration-effect curves in order to address the possible influence of acute receptor desensitization on subsequent analyses. 2. Using the cumulative curve design the following results were obtained: D-AMP-PCBr2P, 2-methylthio-D-AMP-PCCl2P, L-AMP-PCF2P, L-AMP-PCCl2P and LAMP-PCBr2P each behaved as partial agonists. D-AMP-CPP was used as a reference full agonist and these analogues were analysed by the comparative method of Barlow et al. (1967), to provide estimates of affinity and efficacy. 2-Methylthio-L-AMP-PCBr2P was virtually silent as an agonist and was analysed as a competitive antagonist by Schild analysis. 3. Two agonists, L-AMP-PCCl2P and L-AMP-PCBr2P, were analysed by the sequential curve design, and the antagonist effects of one of the agonists, L-AMP-PCBr2P were also analysed using this protocol. The resulting estimates of affinity and efficacy, while similar to those obtained with the cumulative design, indicated that acute desensitization may affect curve definition and estimation of these quantities. 4. The following structure-activity trends emerged: D-analogues tended to have higher efficacy but lower affinity than L-analogues; efficacy varied markedly and inversely with the atomic weight of the halogen while affinity was only minimally affected; 2-methylthio- substitution also reduced efficacy with minimal effect on affinity. 5. The results of this analysis are discussed in terms of the utility of affinity and efficacy information in the classification of purinoceptors and the design of chemical probes for them.

Full text

PDF
490

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ARUNLAKSHANA O., SCHILD H. O. Some quantitative uses of drug antagonists. Br J Pharmacol Chemother. 1959 Mar;14(1):48–58. doi: 10.1111/j.1476-5381.1959.tb00928.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barlow R. B., Scott N. C., Stephenson R. P. The affinity and efficacy of onium salts on the frog rectus abdominis. Br J Pharmacol Chemother. 1967 Sep;31(1):188–196. doi: 10.1111/j.1476-5381.1967.tb01989.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Black J. W., Leff P. Operational models of pharmacological agonism. Proc R Soc Lond B Biol Sci. 1983 Dec 22;220(1219):141–162. doi: 10.1098/rspb.1983.0093. [DOI] [PubMed] [Google Scholar]
  4. Burnstock G., Kennedy C. Is there a basis for distinguishing two types of P2-purinoceptor? Gen Pharmacol. 1985;16(5):433–440. doi: 10.1016/0306-3623(85)90001-1. [DOI] [PubMed] [Google Scholar]
  5. Collis M. G., Jacobson K. A., Tomkins D. M. Apparent affinity of some 8-phenyl-substituted xanthines at adenosine receptors in guinea-pig aorta and atria. Br J Pharmacol. 1987 Sep;92(1):69–75. doi: 10.1111/j.1476-5381.1987.tb11297.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cusack N. J., Hourani S. M., Loizou G. D., Welford L. A. Pharmacological effects of isopolar phosphonate analogues of ATP on P2-purinoceptors in guinea-pig taenia coli and urinary bladder. Br J Pharmacol. 1987 Apr;90(4):791–795. doi: 10.1111/j.1476-5381.1987.tb11233.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Kennedy C. P1- and P2-purinoceptor subtypes--an update. Arch Int Pharmacodyn Ther. 1990 Jan-Feb;303:30–50. [PubMed] [Google Scholar]
  8. Leff P., Prentice D. J., Giles H., Martin G. R., Wood J. Estimation of agonist affinity and efficacy by direct, operational model-fitting. J Pharmacol Methods. 1990 May;23(3):225–237. doi: 10.1016/0160-5402(90)90066-t. [DOI] [PubMed] [Google Scholar]
  9. O'Connor S. E., Wood B. E., Leff P. Characterization of P2x-receptors in rabbit isolated ear artery. Br J Pharmacol. 1990 Nov;101(3):640–644. doi: 10.1111/j.1476-5381.1990.tb14133.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. STEPHENSON R. P. A modification of receptor theory. Br J Pharmacol Chemother. 1956 Dec;11(4):379–393. doi: 10.1111/j.1476-5381.1956.tb00006.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES