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Vol. 299, Issue 3, 908-914, December 2001
Leiden/Amsterdam Center for Drug Research, Division of Medicinal
Chemistry, Vrije Universiteit, Division of Chemistry, Amsterdam, The
Netherlands (K.W., G.B., W.M.B.P.M., H.T., R.L.); Department of Medical
Physics, School of Allied Health Sciences, Faculty of Medicine, Osaka
University, Yamadaoka 1-7, Suita, Osaka, Japan (Y.Y., T.H., A.Y.); and
The R.W. Johnson Pharmaceutical Research Institute, San Diego,
California (T.W.L.)
Agonist-independent activity of G-protein-coupled receptor, also
referred to as constitutive activity, is a well-documented phenomenon
and has been reported recently for both the histamine H1
and H2 receptors. Using SK-N-MC cell lines stably
expressing the human and rat H3 receptors at physiological
receptor densities (500-600 fmol/mg of protein), we show that both the
rat and human H3 receptors show a high degree of
constitutive activity. The forskolin-mediated cAMP production in
SK-N-MC cells is inhibited strongly upon expression of the
Gi-coupled H3 receptor. The cAMP production can
be further inhibited upon agonist stimulation of the H3
receptor and can be enhanced by a variety of H3 antagonists acting as inverse agonists at the H3 receptor.
Thioperamide, clobenpropit, and iodophenpropit raise the cAMP levels in
SK-N-MC cells with potencies that match their receptor binding
affinities. Surprisingly, impentamine and burimamide act as effective
H3 agonists. Modification of the amine group of impentamine
dramatically affected the pharmacological activity of the ligand.
Receptor affinity was reduced slightly for most impentamine analogs,
but the functional activity of the ligands varied from agonist to
neutral antagonist and inverse agonist, indicating that subtle changes
in the chemical structures of impentamine analogs have major impact on
the (de)activation steps of the H3 receptor. In conclusion,
upon stable expression of the rat and human H3 receptor in
SK-N-MC cells constitutive receptor activity is detected. In this
experimental system, H3 receptors ligands, previously
identified as H3 antagonists, cover the whole spectrum of
pharmacological activities, ranging from full inverse agonists to agonists.
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