Agonist analysis of 2‐(carboxycyclopropyl)glycine isomers for cloned metabotropic glutamate receptor subtypes expressed in Chinese hamster ovary cells
Open Access
- 1 October 1992
- journal article
- Published by Wiley in British Journal of Pharmacology
- Vol. 107 (2), 539-543
- https://doi.org/10.1111/j.1476-5381.1992.tb12780.x
Abstract
1 2-(Carboxycyclopropyl)glycines (CCGs) are conformationally restricted glutamate analogues and consist of eight isomers including l- and d-forms. The agonist potencies and selectivities of these compounds for metabotropic glutamate receptors (mGluRs) were studied by examining their effects on the signal transduction of representative mGluR1, mGluR2 and mGluR4 subtypes in Chinese hamster ovary cells expressing the individual cloned receptors. 2 Two extended isomers of l-CCG, l-CCG-I and l-CCG-II, effectively stimulated phosphatidylinositol hydrolysis in mGluR1-expressing cells. The rank order of potencies of these compounds was l-glutamate > l-CCG-I > l-CCG-II. 3 l-CCG-I and l-CCG-II were effective in inhibiting the forskolin-stimulated adenosine 3′:5′-cyclic monophosphate (cyclic AMP) accumulation in mGluR2-expressing cells. Particularly, l-CCG-I was a potent agonist for mGluR2 with an EC50 value of 3 × 10−7 m, which was more than an order of potency greater than that of l-glutamate. 4 l-CCG-I evoked an inhibition of the forskolin-stimulated cyclic AMP production characteristic of mGluR4 with a potency comparable to l-glutamate. 5 In contrast to the above compounds, the other CCG isomers showed no appreciable effects on the signal transduction involved in the three mGluR subtypes. 6 This investigation demonstrates not only the importance of a particular isomeric structure of CCGs in the interaction with the mGluRs but also a clear receptor subtype specificity for the CCG-receptor interaction, and indicates that the CCG isomers would serve as useful agonists for investigation of functions of the mGluR family.Keywords
This publication has 26 references indexed in Scilit:
- Signal transduction and pharmacological characteristics of a metabotropic glutamate receptor, mGluRl, in transfected CHO cellsNeuron, 1992
- Inhibition of Cyclic AMP Formation by a Selective Metabotropic Glutamate Receptor AgonistJournal of Neurochemistry, 1992
- A family of metabotropic glutamate receptorsNeuron, 1992
- A long-term depression of AMPA currents in cultured cerebellar purkinje neuronsNeuron, 1991
- Cloning, Expression, and Gene Structure of a G Protein-Coupled Glutamate Receptor from Rat BrainScience, 1991
- Sequence and expression of a metabotropic glutamate receptorNature, 1991
- A potent metabotropic glutamate receptor agonist: electrophysiological actions of a conformationally restricted glutamate analogue in the rat spinal cord and Xenopus oocytesBrain Research, 1990
- Structure-activity relationships in the development of excitatory ammo acid receptor agonists and competitive antagonistsTrends in Pharmacological Sciences, 1990
- The Excitatory Amino Acid Receptors: Their Classes, Pharmacology, and Distinct Properties in the Function of the Central Nervous SystemAnnual Review of Pharmacology and Toxicology, 1989
- Inhibitory action of glutamic acid on cerebellar interneuronesNature, 1976