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Vol. 55, Issue 3, 453-461, March 1999
Novartis Pharma AG, Nervous System, Basel, Switzerland (S.L., F.G.,
D.R., N.S., P.J.F., I.V., R.K.);
Centre National de la Recherche
Scientifique "Mécanismes Moléculaires des Communications
Cellulaires," Montpellier Cedex, France (L.P., J.-P.P.); and
Novo
Nordisk A/S, Department of Molecular Pharmacology,
Maaloev, Denmark (C.T.)
Metabotropic glutamate receptors (mGluRs) are a family of G
protein-coupled receptors characterized by a large, extracellular N-terminal domain comprising the glutamate-binding site. In the current
study, we examined the pharmacological profile and site of action of
the non-amino-acid antagonist
7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester
(CPCCOEt). CPCCOEt selectively inhibited glutamate-induced increases in
intracellular calcium at human mGluR1b (hmGluR1b) with an apparent
IC50 of 6.5 µM while having no agonist or antagonist activity at hmGluR2, -4a, -5a, -7b, and -8a up to 100 µM. Schild analysis indicated that CPCCOEt acts in a noncompetitive manner by
decreasing the efficacy of glutamate-stimulated phosphoinositide hydrolysis without affecting the EC50 value or Hill
coefficient of glutamate. Similarly, CPCCOEt did not displace
[3H]glutamate binding to membranes prepared from
mGluR1a-expressing cells. To elucidate the site of action, we
systematically exchanged segments and single amino acids between
hmGluR1b and the related subtype, hmGluR5a. Substitution of Thr815 and
Ala818, located at the extracellular surface of transmembrane segment
VII, with the homologous amino acids of hmGluR5a eliminated CPCCOEt
inhibition of hmGluR1b. In contrast, introduction of Thr815 and Ala818
at the homologous positions of hmGluR5a conferred complete inhibition by CPCCOEt (IC50 = 6.6 µM), i.e., a gain of function.
These data suggest that CPCCOEt represents a novel class of G
protein-coupled receptor antagonists inhibiting receptor signaling
without affecting ligand binding. We propose that the interaction of
CPCCOEt with Thr815 and Ala818 of mGluR1 disrupts receptor activation
by inhibiting an intramolecular interaction between the agonist-bound
extracellular domain and the transmembrane domain.
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