Elsevier

Neuropharmacology

Volume 38, Issue 10, October 1999, Pages 1431-1476
Neuropharmacology

Review
Pharmacological agents acting at subtypes of metabotropic glutamate receptors

https://doi.org/10.1016/S0028-3908(99)00092-1Get rights and content

Abstract

Metabotropic (G-protein-coupled) glutamate (mGlu) receptors have now emerged as a recognized, but still relatively new area of excitatory amino acid research. Current understanding of the roles and involvement of mGlu receptor subtypes in physiological/pathophysiological functions of the central nervous system has been recently propelled by the emergence of various structurally novel, potent, and mGlu receptor selective pharmacological agents. This article reviews the evolution of pharmacological agents that have been reported to target mGlu receptors, with a focus on the known receptor subtype selectivities of current agents.

Section snippets

‘Metabotropic’ versus ‘ionotropic’

The use of the term ‘metabotropic’, although now accepted as a useful descriptor for G-protein-coupled glutamate receptors, has provided some discussion over the years. This term originated in the book by McGeer et al. (1978) and article of Eccles and McGeer (1979), where they described two major forms of neurotransmission termed ‘ionotropic’ and ‘metabotropic’. It was proposed that the principle function of an ionotropic substance was to open ionic paths across the post-synaptic membrane,

Background/classification as groups

The recognition that rat brain mRNA could be used to express and measure metabotropic responses to glutamate in the Xenopus oocyte provided the starting place for the cloning of the first mGlu receptor, now termed rat mGlu1a. Rat mGlu1a was expression cloned using a rat cerebellar library by two independent groups (Houamed et al., 1991, Masu et al., 1991). The cloned rat mGlu1a possessed similar pharmacological characteristics to the phosphoinositide-coupled receptors in other rat brain

Agonist pharmacology

The agonist pharmacology associated with mGlu receptors has been defined in both native (brain slice, cultured neuron, spinal cord) preparations and in non-neuronal cell lines expressing recombinant rat or human mGlu receptor subtypes. Previous reviews of mGlu agonist pharmacology include Pin and Duvoisin (1995), Conn and Pin (1997), and Ozawa et al. (1998).

Group I selective competitive antagonists

Early work revealed that (RS)-AP3 was capable of antagonizing excitatory amino acid-induced phosphoinositide (PI) hydrolysis (Schoepp and Johnson, 1989a, Schoepp and Johnson, 1989b) and it was later reported that (S)-AP3 blocked (1S,3R)-ACPD-induced Ca2+ mobilization (Irving et al., 1990). However, it was soon recognized that (S)-AP3 was acting in a non-competitive manner in brain slices preparations (Schoepp et al., 1990) and in some studies (S)-AP3 was inactive on both rat mGlu1a and mGlu5a

Conclusions and future perspectives

The inception of glutamate receptors coupled to metabotropic mechanisms and sensitive assays for their characterization lead to the recognition that selective agents having no ionotropic activities could be designed (i.e. 1S,3R-ACPD, l-CCG-I). However, with the discovery of a family of cloned mGlu receptors many of these early agents were recognized to non-selectively activate or inhibit multiple subtypes of mGlu receptors. As few laboratories have yet to published data on all eight receptor

Acknowledgements

The authors wish to thank Clare L. Schoepp and Genny Harris for their help in the proofing and editing of this manuscipt, Steve Massey and Mathew Valli for help with the illustrations, and Jayne Cartmell for help with our literature search.

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