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Labelling of 5‐Hydroxytryptamine 3 Receptors with a Novel 5‐HT 3 Receptor Ligand, [ 3 H]RS‐42358–197
Author(s) -
Wong Erik H. F.,
Bonhaus Douglas W.,
Wu Irene,
Stefanich Eric,
Eglen Richard M.
Publication year - 1993
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1993.tb03238.x
Subject(s) - quipazine , receptor , ligand (biochemistry) , chemistry , 5 ht receptor , stereochemistry , 5 ht3 receptor , serotonin , biochemistry
RS‐42358–197{( S )‐ N ‐(1‐azabicyclo[2.2.2]oct‐3‐yl)‐2,4,5,6‐tetrahydro‐1 H ‐benzo[de]isoquinolin‐1‐one hydrochloride} displaced the prototypic 5‐hydroxytryptamine 3 (5‐HT 3 ) receptor ligand [ 3 H]quipazine in rat cerebral cortical membranes with an affinity ( pK i ) of 9.8 ± 0.1, while having weak affinity ( pK i < 6.0) in 23 other receptor binding assays. [ 3 H]RS‐42358–197 was then utilized to label 5‐HT 3 receptors in a variety of tissues. [ 3 H]RS‐42358–197 labelled high‐affinity and saturable binding sites in membranes from rat cortex, NG108–15 cells, and rabbit ileal myenteric plexus with affinities ( K D ) of 0.12 ± 0.01, 0.20 ± 0.01, and 0.10 ± 0.01 n M and densities ( B max ) of 16.0 ± 2.0, 660 ± 74, and 88 ± 12 fmol/mg of protein, respectively. The density of sites labelled in each of these tissues with [ 3 H]RS‐42358–197 was similar to that labelled with [ 3 H]GR 65630, but was significantly less than that found with [ 3 H]‐quipazine. The binding of [ 3 H]RS‐42358–197 had a pharmacological profile similar to that of [ 3 H]quipazine, as indicated by the rank order of displacement potencies: RS‐42358–197 > ( S )‐zacopride > tropisetron > ( R )‐zacopride > ondansetron > MDL72222 > 5‐HT. However, differences in 5‐HT 3 receptors of different tissues and species were detected on the basis of statistically significant differences in the affinities of phenylbiguanide, and 1‐( m ‐chlorophenyl)biguanide when displacing [ 3 H]RS‐42358‐197 binding. [ 3 H]RS‐42358–197 also labelled a population ( B max = 91 ± 17 fmol/mg of protein) of binding sites in guinea pig myenteric plexus membranes, with lower affinity ( K D = 1.6 ± 0.3 n M ) than those in the other preparations. Moreover, the rank order of displacement potencies of 15 5‐HT 3 receptor ligands in guinea pig ileum was found not to be identical to that in other tissues. Binding studies carried out with [ 3 H]RS‐42358–197 have detected differences in 5‐HT 3 receptor binding sites in tissues of different species and further underscore the unique nature of the guinea pig 5‐HT 3 receptor.