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. 1998 Jul;124(6):1300–1306. doi: 10.1038/sj.bjp.0701946

Functional characterisation of the human cloned 5-HT7 receptor (long form); antagonist profile of SB-258719

David R Thomas 1,*, Susan A Gittins 1, Lissa L Collin 1, Derek N Middlemiss 1, Graham Riley 1, Jim Hagan 1, Israel Gloger 2, Catherine E Ellis 2, Ian T Forbes 3, Anthony M Brown 1
PMCID: PMC1565501  PMID: 9720804

Abstract

  1. The functional profile of the long form of the human cloned 5-HT7 receptor (designated h5-HT7(a)) was investigated using a number of 5-HT receptor agonists and antagonists and compared with its binding profile. Receptor function was measured using adenylyl cyclase activity in washed membranes from HEK293 cells stably expressing the recombinant h5-HT7(a) receptor.

  2. The receptor binding profile, determined by competition with [3H]-5-CT, was consistent with that previously reported for the h5-HT7(a) receptor. The selective 5-HT7 receptor antagonist SB-258719 ((R)-3,N-Dimethyl-N-[1-methyl-3-(4-methylpiperidin-1-yl)propyl]benzene sulfonamide) displayed high affinity (pKi 7.5) for the receptor.

  3. In the adenylyl cyclase functional assay, 5-CT and 8-OH-DPAT were both full agonists compared to 5-HT and the rank order of potency for agonists (5-CT>5-HT>8-OH-DPAT) was the same in functional and binding studies.

  4. Risperidone, methiothepin, mesulergine, clozapine, olanzapine, ketanserin and SB-258719 antagonised surmountably 5-CT-stimulated adenylyl cyclase activity. Schild analysis of the antagonism by SB-258719 gave a pA2 of 7.2±0.2 and slope not significantly different from 1, consistent with competitive antagonism.

  5. The same antagonists also inhibited basal adenylyl cyclase activity with a rank order of potency in agreement with those for antagonist potency and binding affinity. Both SB-258719 and mesulergine displayed apparent partial inverse agonist profiles compared to the other antagonists tested. These inhibitory effects of antagonists appear to be 5-HT7 receptor-mediated and to reflect inverse agonism.

  6. It is concluded that in this expression system, the h5-HT7(a) receptor shows the expected binding and functional profile and displays constitutive activity, revealing inverse agonist activity for a range of antagonists.

Keywords: Human 5-HT7(a) receptor, long splice variant, functional characterisation, adenylyl cyclase, [3H]-5-CT binding, constitutive receptor activity, inverse agonism, SB-258719

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