COMPOUND A is a positive allosteric modulator of mGluR2 and has a procognitive profile.The present study investigated the effects of COMPOUND A in two clinically relevant cognition models, Latent Inhibition (LI) and Auditory Evoked Potentials (AEPs). LI and AEP are cross-species phenomena that are deficient in schizophrenia and that can be recorded in both rodents and human. Deficits in LI are believed to reflect aberrant switching/distractibility akin to schizophrenia. Deficiencies in AEPs have been regarded as manifestations of impaired sensory and attentional processing, leading to disturbed perception in patients with schizophrenia. In the LI model, amphetamine disrupted the learning behavior. COMPOUND A reversed this amphetamine deficit at doses of 1 and 10 mg/kg (po). A reversal of amphetamine disrupted LI was also seen with haloperidol (0.3 mg/kg ip). In the AEP model, amphetamine caused a disruption of paired auditory stimuli gating in a manner similar to that seen in schizophrenia. Whereas COMPOUND A did not affect baseline (vehicle control) gating (at 3 mg/kg po), COMPOUND A did reverse the amphetamine disrupted gating at doses of 0.3 and 3 mg/kg po.Reversal of amphetamine disrupted LI is thought to be an indicator of improved selective attention, and/or positive symptom efficacy. As our companion poster (Black et al ) has indicated minimal effects of COMPOUND A in positive symptom models and robust improvements in cognition, we propose the effects of COMPOUND A here represent pro-cognitive activity. In agreement with this effect is the reversal of amphetamine-disrupted gating by COMPOUND A that could be indicative of sustained attention. As both techniques (LI and AEP) can be performed in a similar manner in humans, this opens up the ability to perform dose ranging studies for COMPOUND A in clinical trials; either by disrupting these phenomena with amphetamine in Phase I or Phase II studies in patients with natural deficits.

Antagonism of the adenosine A2A receptor affords a possible treatment of Parkinson’s disease. In the course of investigating pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A2A antagonists, we prepared [1,2,4]-triazolo[4,3-c]pyrimidin-3-ones with potent and selective (vs A1) A2A antagonist activity. Structure–activity relationships are described for this series.