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Characterization of 5‐HT 3 and ‘atypical’ 5‐HT receptors mediating guinea‐pig ileal contractions in vitro
Author(s) -
Eglen R.M.,
Swank S.R.,
Walsh L.K.M.,
Whiting R.L.
Publication year - 1990
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1990.tb14113.x
Subject(s) - quipazine , methysergide , 5 ht receptor , agonist , receptor , chemistry , serotonin , granisetron , medicine , endocrinology , biology , antiemetic , vomiting
1 Neuronal 5‐hydroxytryptamine (5‐HT) receptors mediating contraction of guinea‐pig ileal segments have been characterized in vitro by the use of methysergide to block 5‐HT 1 ‐like and 5‐HT 2 receptors. Concentration‐response curves to 5‐HT were biphasic (first phase, defined as those responses occurring between 1 n m and 0.32 μ m 5‐HT, –log EC 50 = 7.15 ± 0.08; second phase, defined as these responses occurring between 0.32 μ m and 32 μ m 5‐HT, –log EC 50 = 5.32 ± 0.03) but monophasic to 5‐methoxytryptamine (−log EC 50 = 7.0 ± 0.08) and 2 methyl 5‐HT (−log EC 50 = 5.2 ± 0.13). The maximal response of the first phase to 5‐HT and the maximal response to 5‐methoxytryptamine were 30 ± 4% and 35 ± 5% respectively of the maximum response to the second phase of the 5‐HT concentration‐effect curve (set at 100%). In contrast, the maximal response to 2‐methyl‐5‐HT equalled that obtained with 5‐HT (second phase). 2 The responses comprising the second phase of the concentration‐effect curve to 5‐HT were antagonized by 1 μ m ICS 205–930, ondansetron, granisetron, quipazine, N‐methyl‐quipazine and ( R,S )‐zacopride and the following pK B values, with 5‐HT as the agonist, were obtained at the 5‐HT 3 receptor: ICS 205–930 7.61 ± 0.05, ondansetron 6.90 ± 0.04, granisetron 7.90 ± 0.04, (S)‐zacopride 8.11 ± 0.06, ( R,S )‐zacopride 7.64 ± 0.11, and ( R )‐zacopride 7.27 ± 0.06. 3 Under conditions of 5‐HT 1 ‐like, 5‐HT 2 and 5‐HT 3 receptor blockade, the following rank order of agonism was observed: 5‐HT > 5‐methoxytryptamine = renzapride > ( S )‐zacopride > ( R,S )‐zacopride > 5‐carboxamidotryptamine > BRL 24682 > ( R )‐zacopride > metoclopramide > 2‐methyl‐5‐HT ≫ sulpiride. 8‐Dihydroxydiphenylaminotetralin (8‐OHDPAT), GR 43175, N,N‐dipropyl‐5‐carboxamidotryptamine, ondansetron, ICS 205–930, granisetron, quipazine and N‐methyl‐quipazine were inactive as agonists and antagonists. Relative to 5‐HT, ( R,S )‐zacopride acted as a partial agonist (intrinsic activity, α = 0.80; –log EC 50 = 6.3 ± 0.12; –log K A = 6.1 ± 0.03) as did ( R )‐zacopride (α = 0.4, –log EC 50 5.7 ± 0.08, –log K A = 5.5 ± 0.11). ( S )‐zacopride acted as a full agonist (−log EC 50 = 6.9 ± 0.03). ICS 205–930 (3 μ m ) antagonized competitively responses to 5‐HT, 5 methoxytryptamine, ( R,S )‐ and ( S )‐zacopride and 5‐carboxamidotryptamine yielding –log K B estimates ranging from 6.1–6.5. 4 It is concluded that two different 5‐HT receptors mediate excitatory neuronal responses in the guinea‐pig ileum. 5‐HT 3 receptors mediate the second phase of the biphasic concentration‐response curve, whereas a receptor with properties distinct from the 5‐HT 1 ‐like, 5‐HT 2 and 5‐HT 3 subtypes mediates the initial phase of the concentration‐response curve. This receptor, which exhibits a close similarity to the 5‐HT 4 subtype is: (1) stimulated by 5‐methoxytryptamine but not 2‐methyl‐5‐HT; (2) stimulated selectively by certain substituted benzamides; (3) recognizes the optical isomers of zacopride and (4) is blocked by relatively high concentrations ICS 205–930 (pK B = 6.0–6.5) but not ondansetron, granisetron, quipazine or N‐methyl‐quipazine.