Biochemical and electrophysiological studies on ( S)-(+)-2-(3′-carboxybicyclo[1.1.1]pentyl)-glycine (CBPG), a novel mGlu 5 receptor agonist endowed with mGlu 1 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 mGlu 5a receptor transfected cells, CBPG behaved as a partial agonist, while in mGlu 1α receptor transfected cells, it behaved as a glutamate antagonist. No effect was found on cAMP formation in cells transfected with mGlu 2 receptors or mGlu 4 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 μM) caused depolarization, increased cell input resistance, and decreased action potential frequency adaptation and afterhyperpolarization. DHPG (3–100 μM), an agonist of both mGlu 1 and mGlu 5 receptors, and CHPG (1000 μM), a low affinity mGlu 5 agonist, produced qualitatively similar effects. The actions of CBPG or CHPG were not modified by AIDA (300 μM), a selective mGlu 1 receptor antagonist. Our results suggest that CBPG could be a useful tool for discriminating between mGlu 1 receptor and mGlu 5 receptor effects and that mGlu 5 receptors are the receptors which are mainly responsible for the direct excitatory effects of mGlu receptor agonists on CA1 pyramidal cells.