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5-Hydroxytryptamine receptors with a 5-HT6 receptor-like profile stimulating adenylyl cyclase activity in pig caudate membranes

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Abstract

This study deals with the characterization of 5-hydroxytryptamine (5-HT, serotonin) receptors positively linked to adenylyl cyclase in membranes from pig brain caudate. 5-HT and related agonists induced a concentration-dependent stimulation of adenylyl cyclase activity in pig caudate membranes, with the following rank order of potency (mean pEC50 values): 5-HT (7.1) ≥ 5-methoxytryptamine (6.9) > 5-carboxamidotryptamine (5.6) > sumatriptan (<5). Maximal stimulation by 5-HT averaged 35 pmol cyclic AMP/min/mg protein over a basal activity of 159 pmol cyclic AMP/min/mg protein. 5-Methoxytryptamine and 5-carboxamidotryptamine had similar efficacies to that of 5-HT, whereas sumatriptan was about half efficacious. Other compounds known as agonists at some 5-HT receptors were weakly potent (mean pEC50 values <5). They include the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), the 5-HT4 receptor agonist, renzapride and the 5-HT2 receptor agonist, (1-(2,5-dimethoxy-4-iodophenyl)-2 aminopropane) (DOI). In antagonist studies, methiothepin (0.1 and 1 μmol/l) shifted the 5-HT curve to the right with no depression of the Emax, yielding pKB values of 7.4–8.0. Clozapine (1 μmol/l) also produced surmountable antagonism of 5-HT-induced effects (pKB 6.9). Ketanserin (10 μmol/l) weakly antagonized 5-HT (pKB 5.0). The 5-HT4 receptor antagonists, tropisetron (ICS 205–930) and SDZ 205–557 (2-methoxy-4-amino-5-chloro-benzoic acid 2-(diethylamino) ethyl ester), each at 1 μmol/l, did not significantly alter the concentration-response curve of 5-HT. The present receptor shares some characteristics of the recently cloned 5-HT6 receptor (Monsma et al. (1993) Mol Pharmacol 43:320–327): similar pharmacological profile, location (striatum) and ability to stimulate adenylyl cyclase. It may thus represent the functional 5-HT6 receptor in its natural environment.

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  1. Christian Waeber

    Present address: Stroke Research Laboratory, Massachusetts General Hospital, Harvard Medical School, 02114, Boston, MA, USA

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  1. Preclinical Research, 386/744, Sandoz Pharma Ltd., CH-4002, Basel, Switzerland

    Philippe Schoeffter & Christian Waeber

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  1. Philippe Schoeffter
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  2. Christian Waeber
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Correspondence to: P. Schoeffter at the above address

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Schoeffter, P., Waeber, C. 5-Hydroxytryptamine receptors with a 5-HT6 receptor-like profile stimulating adenylyl cyclase activity in pig caudate membranes. Naunyn-Schmiedeberg's Arch Pharmacol 350, 356–360 (1994). https://doi.org/10.1007/BF00178951

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  • DOI: https://doi.org/10.1007/BF00178951

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