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

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 CAl pyramidal cells of the hippocampus were also evaluated. In mGlu(5a) receptor transfected cells, CBPG behaved as a partial agonist, while in mGlu(1 alpha) 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 CAl pyramidal cells of the hippocampus, CBPG (50-100 mu M) caused depolarization, increased cell input resistance, and decreased action potential frequency adaptation and afterhyperpolarization. DHPG (3-100 mu M), an agonist of both mGlu, and mGlu, receptors, and CHPG (1000 mu M), a low affinity mGlu, agonist, produced qualitatively similar effects. The actions of CBPG or CHPG were not modified by AIDA (300 mu M), a selective mClu(1) receptor antagonist. Our results suggest that CBPG could be a useful tool for discriminating between mGlu(1) receptor and mClu(5) receptor effects and that mGlu(1) receptors are the receptors which are mainly responsible for the direct excitatory effects of mGlu receptor agonists on CAl pyramidal cells. (C) 1999 Elsevier Science Ltd. All rights reserved.