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

Thomas, David R. ; Gittins, Susan A. ; Collin, Lissa L. ; Middlemiss, Derek N. ; Riley, Graham ; Hagan, Jim ; Gloger, Israel ; Ellis, Catherine E. ; Forbes, Ian T. ; Brown, Anthony M.

British journal of pharmacology, 1998-07, Vol.124 (6), p.1300-1306 [Periódico revisado por pares]

Oxford, UK: Blackwell Publishing Ltd

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Título:
Functional characterisation of the human cloned 5‐HT7 receptor (long form); antagonist profile of SB‐258719
Autor: Thomas, David R. ; Gittins, Susan A. ; Collin, Lissa L. ; Middlemiss, Derek N. ; Riley, Graham ; Hagan, Jim ; Gloger, Israel ; Ellis, Catherine E. ; Forbes, Ian T. ; Brown, Anthony M.
Assuntos: [3H]‐5‐CT binding ; adenylyl cyclase ; Adenylyl Cyclases - metabolism ; Biological and medical sciences ; Cell Line ; Cloning, Molecular ; constitutive receptor activity ; functional characterisation ; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism ; Human 5‐HT7(a) receptor ; Humans ; inverse agonism ; long splice variant ; Medical sciences ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Pharmacology. Drug treatments ; Piperidines - pharmacology ; Protein Binding ; Receptors, Serotonin - genetics ; Receptors, Serotonin - metabolism ; Recombinant Proteins - antagonists & inhibitors ; Recombinant Proteins - genetics ; Recombinant Proteins - metabolism ; SB‐258719 ; Serotonin Antagonists - pharmacology ; Serotoninergic system ; Sulfonamides - pharmacology
É parte de: British journal of pharmacology, 1998-07, Vol.124 (6), p.1300-1306
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Descrição: 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. British Journal of Pharmacology (1998) 124, 1300–1306; doi:10.1038/sj.bjp.0701946
Editor: Oxford, UK: Blackwell Publishing Ltd
Idioma: Inglês

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

Thomas, David R. ; Gittins, Susan A. ; Collin, Lissa L. ; Middlemiss, Derek N. ; Riley, Graham ; Hagan, Jim ; Gloger, Israel ; Ellis, Catherine E. ; Forbes, Ian T. ; Brown, Anthony M.

Oxford, UK: Blackwell Publishing Ltd

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