Biochemical and electrophysiological studies on (S)-(+)-2-(3'- carboxybicyclo[1.1.1]pentyl)-glycine (CBPG), a novel mGlu5 receptor agonist endowed with mGlu1 receptor antagonist activity.

Abstract: The pharmacological profile of (S)-(+)-2-(3'-carboxybicyclo[1.1.1]pentyl)-glycine (CBPG) and of other group 1 metabotropic glutamate (mGlu) receptor agents were studied in BHK cells transfected with mGlu receptor subtypes or in native receptors in brain slices by measuring second messenger responses. The mGlu receptor-mediated changes in the electrophysiological properties of CA1 pyramidal cells of the hippocampus were also evaluated. In mGlu5a receptor transfected cells, CBPG behaved as a partial agonist, while in mGlu1alpha receptor transfected cells, it behaved as a glutamate antagonist. No effect was found on cAMP formation in cells transfected with mGlu2 receptors or mGlu4 receptors. In brain slices, CBPG neither affected phospholipase D-coupled glutamate receptors nor did it modify the responses to ionotropic receptor stimulation (at concentrations up to 1 mM). When tested in CA1 pyramidal cells of the hippocampus, CBPG (50-100 microM) caused depolarization, increased cell input resistance, and decreased action potential frequency adaptation and afterhyperpolarization. DHPG (3-100 microM), an agonist of both mGlu1 and mGlu5 receptors, and CHPG (1000 microM), a low affinity mGlu5 agonist, produced qualitatively similar effects. The actions of CBPG or CHPG were not modified by AIDA (300 microM), a selective mGlu1 receptor antagonist. Our results suggest that CBPG could be a useful tool for discriminating between mGlu1 receptor and mGlu5 receptor effects and that mGlu5 receptors are the receptors which are mainly responsible for the direct excitatory effects of mGlu receptor agonists on CA1 pyramidal cells