Anxiolytic activity of glycine-B antagonists and partial agonists--no relation to intrinsic activity in the patch clamp.

On the basis of animal models, anxiety was one of the first suggested clinical applications of partial agonists of the glycineB site coupled to the NMDA receptor. It is not certain, however, whether these findings can be extended to full glycineB antagonists and what is the relation between intrinsic activity (degree of NMDA receptor antagonism) and anxiolytic effect. In the present study several NMDA receptor antagonists, including several glycineB antagonists/partial agonists, were tested for anxiolytic activity in the Vogel conflict test and the elevated plus-maze. Additionally, the intrinsic activities of the glycineB partial agonists used [ACPC, (R,+)-HA-966 and D-cycloserine] were compared in patch-clamp experiments in cultured neurones. In the plus-maze the most striking increase in the time spent in open arms (index of anxiolytic effect) was seen after diazepam and D-cycloserine (at doses that did not change locomotion). Also reliable (dose-dependent), although weaker, anxiolytic activity was produced by the uncompetitive NMDA receptor antagonist (+)MK-801 and the competitive antagonist CGP 39551. Modest anxiolytic-like effect in the plus-maze was also observed after the glycineB antagonist L-701,324 and the partial agonist (+,R)-HA-966. Uncompetitive antagonists memantine and amantadine, the glycineB partial agonist ACPC (up to 600 mg/kg) or the full antagonists MRZ 2/570, MRZ 2/571 and MRZ 2/576 had no effect. In the Vogel conflict test neither memantine, nor any of the full glycineB antagonists tested (L-701,324 and MRZ 2/576), showed anxiolytic activity. Patch-clamp studies revealed that the intrinsic activity of (+,R)-HA-966, D-cycloserine and ACPC was 13, 57 and 92%, respectively, as compared to that of glycine itself (100%). In conclusion, for the agents tested there is no clear relation between the levels of intrinsic activity, i.e. degree of NMDA receptor inhibition, and anxiolytic activity. Moreover, L-701,324 and MRZ-type glycineB full antagonists do not exchibit anxiolytic activity in the elevated plus-maze and Vogel conflict test.