1 The biochemical and pharmacological properties of 5‐HT3 receptors in homogenates of NG108‐15 and NCB‐20 neuroblastoma cells and rat cerebral cortex have been ascertained by the use of (3H)‐quipazine and (3H)‐GR65630 binding. 2 In NG108‐15 and NCB‐20 cell homogenates, (3H)‐quipazine bound to a single class of high affinity (NG108‐15: Kd = 6.2 ± 1.1 nm, n = 4; NCB‐20: Kd = 3.0 ± 0.9 nm, n = 4; means ± s.e.means) saturable (NG108‐15: Bmax = 1340 ± 220 fmol mg−1 protein; NCB‐20: Bmax = 2300 ± 200 fmol mg−1 protein) binding sites. In rat cortical homogenates, (3H)‐quipazine bound to two populations of binding sites in the absence of the 5‐hydroxytryptamine (5‐HT) uptake inhibitor, paroxetine (Kd1 = 1.6 ± 0.5 nm, Bmax1 = 75 ± 14 fmol mg−1 protein; Kd2 = 500 ± 300 nm, Bmax2 = 1840 ± 1040 fmol mg−1 protein, n = 3), and to a single class of high affinity binding sites (Kd = 2.0 ± 0.5 nm, n = 3; Bmax = 73 ± 6 fmol mg−1 protein) in the presence of paroxetine. The high affinity (nanomolar) component probably represented 5‐HT3 binding sites and the low affinity component represented 5‐HT uptake sites. 3 (3H)‐paroxetine bound with high affinity (Kd = 0.02 ± 0.003 nm, n = 3) to a site in rat cortical homogenates in a saturable (Bmax = 323 ± 45 fmol mg−1 protein, n = 3) and reversible manner. Binding to this site was potently inhibited by 5‐HT uptake blockers such as paroxetine and fluoxetine (pKi s = 8.6–9.9), while 5‐HT3 receptor ligands exhibited only low affinity (pKi < 7). No detectable specific (3H)‐paroxetine binding was observed in NG108‐15 or NCB‐20 cell homogenates. 4 (3H)‐quipazine binding to homogenates of NG108‐15, NCB‐20 cells and rat cortex (in the presence of 0.1 μm paroxetine) exhibited similar pharmacological characteristics. 5‐HT3 receptor antagonists competed for (3H)‐quipazine binding with high nanomolar affinities in the three preparations and the rank order of affinity was: (S)‐zacopride > quarternized ICS 205–930 ≥ granisetron > ondansetron > ICS 205–209 ≥ (R)‐zacopride > quipazine > renzapride > MDL‐72222 > butanopride > metoclopramide. 5 (3H)‐GR65630 labelled a site in NCB‐20 cell homogenates with an affinity (Kd = 0.7 ± 0.1 nm, n = 4) and density (Bmax = 1800 ± 1000 fmol mg−1 protein) comparable to that observed with (3H)‐quipazine. Competition studies also indicated a good correlation between the pharmacology of 5‐HT3 binding sites when (3H)‐GR65630 and (3H)‐quipazine were used in these cells. 6 In conclusion, (3H)‐quipazine labelled 5‐HT3 receptor sites in homogenates of NG108‐15 cells, NCB‐20 cells and rat cerebral cortex. In rat cortical homogenates, (3H)‐quipazine also bound to 5‐HT uptake sites, which could be blocked by 0.1 μm paroxetine. The pharmacological specificity of the 5‐HT3 receptor labelled by (3H)‐quipazine was similar in the neuroblastoma cells and rat cortex and was substantiated in NCB‐20 cells by the binding profile of the selective 5‐HT3 receptor antagonist, (3H)‐GR65630.
British Journal of Pharmacology – Wiley
Published: Apr 1, 1991
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