Selected aspects of group I mGlu receptor negative and positive modulators
Several mGluR5 modulators have became available showing acceptable pharmacokinetics and selectivity. There are negative allosteric modulators such as MTEP, MPEP, or fenobam (NAMs) or positive allosteric modulators (PAMs) such as CDPPB or ADX47273. We performed a verifi cation of the therapeutic potential of these modulators using various behavioural methods. mGluR5 NAMs produced analgesic effects in several pain models such as formalin, and Freund adjuvant model of infl ammatory pain. Additionally they very strongly attenuated L-DOPA induced dyskinesia and produced anxiolytic activity in some models of anxiety such as fear potentiated startle, context freezing. However, effi cacy was not better then respective indication reference agents. mGluR5 PAMs are expected to have antipsychoticlike activity and improve learning. These expectations can be in our hands only partially fulfi lled for schizophrenia (positive effects in amphetamine-induced hyperactvitivity, apomorphine-induced prepulse inhibition, or conditioned avoidance response inhibition). No clear positive effect was observed in models of cognition. Recently, several clinical trials with metabotropic glutamate receptor type 5 negative modulators showed positive effects in indications such as migraine, refl ux and L-DOPA-induced dyskinesia. This regards ADX 10059 from Addex and AFQ056 from Novartis indicating that their introduction to clinical practice may be just a matter of short time.