Agonist interactions with 5‐HT 3 receptor recognition sites in the rat entorhinal cortex labelled by structurally diverse radioligands

Agonist interactions with 5‐HT 3 receptor recognition sites in the rat entorhinal cortex... 1 The pharmacological properties of 5‐HT3 receptor recognition sites labelled with (3H)‐(S)‐zacopride, (3H)‐LY278,584, (3H)‐granisetron and (3H)‐GR67330 in membranes prepared from the rat entorhinal cortex were investigated to assess the presence of cooperativity within the 5‐HT3 receptor complex. 2 In rat entorhinal cortex homogenates, (3H)‐(S)‐zacopride, (3H)‐LY278,584, (3H)‐granisetron and (3H)‐GR67330 labelled homogeneous densities of recognition sites (defined by granisetron, 10 μm) with high affinity (Bmax = 75 ± 5, 53 ± 5, 92 ± 6 and 79 ± 6 fmol mg−1 protein, respectively; pKd = 9.41 ± 0.04, 8.69 ± 0.14, 8.81 ± 0.06 and 10.14 ± 0.04 for (3H)‐(S)‐zacopride, (3H)‐LY278,584, (3H)‐granisetron and (3H)‐GR67330, respectively, n = 3–8). 3 Quipazine and granisetron competed for the binding of each of the radioligands in the rat entorhinal cortex preparation at low nanomolar concentrations (pIC50; quipazine 9.38–8.51, granisetron 8.62–8.03), whilst the agonists, 5‐hydroxytryptamine (5‐HT), phenylbiguanide (PBG) and 2‐methyl‐5‐HT competed at sub‐micromolar concentrations (pIC50; 5‐HT 7.16–6.42, PBG 7.52–6.40, 2‐methyl‐5‐HT 7.38–6.09). 4 Competition curves generated with increasing concentrations of quipazine, PBG, 5‐HT and 2‐methyl‐5‐HT displayed Hill coefficients greater than unity when the 5‐HT3 receptor recognition sites in the entorhinal cortex preparation were labelled with (3H)‐LY278,584, (3H)‐granisetron and (3H)‐GR67330. These competing compounds displayed Hill coefficients of around unity when the sites were labelled with (3H)‐(S)‐zacopride. Competition for the binding of (3H)‐(S)‐zacopride, (3H)‐LY278,584, (3H)‐granisetron and (3H)‐GR67330 by granisetron generated Hill coefficients around unity. 5 The nature of the interaction of competing compounds (quipazine, granisetron, PBG, 5‐HT, 2‐methyl‐5‐HT) for the (3H)‐(S)‐zacopride binding site in the rat entorhinal cortex preparation was not altered by the removal of the Krebs ions or the addition of the monoamine oxidase inhibitor, pargyline, to the HEPES/Krebs buffer. 6 In conclusion, the present studies provide further evidence towards the presence of cooperativity within the 5‐HT3 receptor macromolecule and indicate that either (3H)‐(S)‐zacopride labels a different site on the receptor complex from (3H)‐LY278,584, (3H)‐granisetron or (3H)‐GR67330, or it binds in such a manner as to prevent the conformatory change in the receptor protein responsible for the cooperative binding of agonists (and quipazine). http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Pharmacology Wiley

Agonist interactions with 5‐HT 3 receptor recognition sites in the rat entorhinal cortex labelled by structurally diverse radioligands

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Publisher
Wiley
Copyright
1992 British Pharmacological Society
ISSN
0007-1188
eISSN
1476-5381
DOI
10.1111/j.1476-5381.1992.tb14283.x
Publisher site
See Article on Publisher Site

Abstract

1 The pharmacological properties of 5‐HT3 receptor recognition sites labelled with (3H)‐(S)‐zacopride, (3H)‐LY278,584, (3H)‐granisetron and (3H)‐GR67330 in membranes prepared from the rat entorhinal cortex were investigated to assess the presence of cooperativity within the 5‐HT3 receptor complex. 2 In rat entorhinal cortex homogenates, (3H)‐(S)‐zacopride, (3H)‐LY278,584, (3H)‐granisetron and (3H)‐GR67330 labelled homogeneous densities of recognition sites (defined by granisetron, 10 μm) with high affinity (Bmax = 75 ± 5, 53 ± 5, 92 ± 6 and 79 ± 6 fmol mg−1 protein, respectively; pKd = 9.41 ± 0.04, 8.69 ± 0.14, 8.81 ± 0.06 and 10.14 ± 0.04 for (3H)‐(S)‐zacopride, (3H)‐LY278,584, (3H)‐granisetron and (3H)‐GR67330, respectively, n = 3–8). 3 Quipazine and granisetron competed for the binding of each of the radioligands in the rat entorhinal cortex preparation at low nanomolar concentrations (pIC50; quipazine 9.38–8.51, granisetron 8.62–8.03), whilst the agonists, 5‐hydroxytryptamine (5‐HT), phenylbiguanide (PBG) and 2‐methyl‐5‐HT competed at sub‐micromolar concentrations (pIC50; 5‐HT 7.16–6.42, PBG 7.52–6.40, 2‐methyl‐5‐HT 7.38–6.09). 4 Competition curves generated with increasing concentrations of quipazine, PBG, 5‐HT and 2‐methyl‐5‐HT displayed Hill coefficients greater than unity when the 5‐HT3 receptor recognition sites in the entorhinal cortex preparation were labelled with (3H)‐LY278,584, (3H)‐granisetron and (3H)‐GR67330. These competing compounds displayed Hill coefficients of around unity when the sites were labelled with (3H)‐(S)‐zacopride. Competition for the binding of (3H)‐(S)‐zacopride, (3H)‐LY278,584, (3H)‐granisetron and (3H)‐GR67330 by granisetron generated Hill coefficients around unity. 5 The nature of the interaction of competing compounds (quipazine, granisetron, PBG, 5‐HT, 2‐methyl‐5‐HT) for the (3H)‐(S)‐zacopride binding site in the rat entorhinal cortex preparation was not altered by the removal of the Krebs ions or the addition of the monoamine oxidase inhibitor, pargyline, to the HEPES/Krebs buffer. 6 In conclusion, the present studies provide further evidence towards the presence of cooperativity within the 5‐HT3 receptor macromolecule and indicate that either (3H)‐(S)‐zacopride labels a different site on the receptor complex from (3H)‐LY278,584, (3H)‐granisetron or (3H)‐GR67330, or it binds in such a manner as to prevent the conformatory change in the receptor protein responsible for the cooperative binding of agonists (and quipazine).

Journal

British Journal of PharmacologyWiley

Published: Feb 1, 1992

References

  • Identification and characterisation of 5‐hydroxytryptamine 3 recognition sites in human brain tissue
    BARNES, BARNES; BARNES, BARNES; COSTALL, COSTALL; IRONSIDE, IRONSIDE; NAYLOR, NAYLOR
  • ( 3 H)Zacopride: ligand for the identification of 5‐HT 3 recognition sites
    BARNES, BARNES; COSTALL, COSTALL; NAYLOR, NAYLOR
  • Characteristics of 5‐HT 3 binding sites in NG108–15, NCB‐20 neuroblastoma cells and rat cerebral cortex using ( 3 H)‐quipazine and ( 3 H)‐GR65630 binding
    SHARIF, SHARIF; WONG, WONG; LOURY, LOURY; STEFANICH, STEFANICH; MICHEL, MICHEL; EGLEN, EGLEN; WHITING, WHITING

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