Both mGluR5 and mGluR1 antagonists are effective in models of pain and anxiety. However, an mGluR1 antagonist was more efficacious than the two mGluR5 antagonists in the pain models, which, conversely, appeared more efficacious in the anxiety models. These findings support the potential utility of mGluR5 and mGluR1 antagonists for both the treatment of chronic pain and as novel anxiolytics.

Blockade of adenosine receptors can reduce cerebral infarct size in the model of global ischaemia. Using the potent and selective A2A adenosine receptor antagonist, SCH 58261, we assessed whether A2A receptors are involved in the neuronal damage following focal cerebral ischaemia as induced by occluding the left middle cerebral artery. SCH 58261 (0.01 mg/kg either i.p. or i.v.) administered to normotensive rats 10 min after ischaemia markedly reduced cortical infarct volume as measured 24 h later (30% vs controls, p < 0.05). Similar effects were observed when SCH 58261 (0.01 mg/kg, i.p.) was administered to hypertensive rats (28% infarct volume reduction vs controls, p < 0.05). Neuroprotective properties of SCH 58261 administered after ischaemia indicate that blockade of A2A adenosine receptors is a potentially useful biological target for the reduction of brain injury.

The adenosine A 2A receptor has been implicated in the underlying biology of various neurological and psychiatric disorders, including Parkinson's disease (PD) and depression. Preladenant and SCH 412348 [7-[2-[4-2,4- ,2,4]triazolo [1,5-c]pyrimidin-5-amine] are potent competitive antagonists of the human A 2A receptor (K i ϭ 1.1 and 0.6 nM, respectively) and have Ͼ1000-fold selectivity over all other adenosine receptors, making these compounds the most selective A 2A receptor antagonists reported to date. Both compounds attenuate hypolocomotion induced by the A 2A receptor agonist CGS-21680 [2-[p-(2-carboxyethyl)phenethylamino]-5Ј-N-ethylcarboxamidoadenosine], suggesting that they inhibit A 2A receptor activity in vivo. Their high degree of selectivity and robust in vivo activity make preladenant and SCH 412348 useful tools to investigate the role of the A 2A receptor system in animal models of PD and depression. Oral administration of preladenant and SCH 412348 (0.1-1 mg/kg) to rats potentiated 3,4-dihydroxy-L-phenylalanine (L-Dopa)-induced contralateral rotations after 6-hydroxydopamine lesions in the medial forebrain bundle and potently attenuated the cataleptic effects of haloperidol. Preladenant (1 mg/kg) inhibited L-Dopa-induced behavioral sensitization after repeated daily administration, which suggests a reduced risk of the development of dyskinesias. Finally, preladenant and SCH 412348 exhibited antidepressant-like profiles in models of behavioral despair, namely the mouse tail suspension test and the mouse and rat forced swim test. These studies demonstrate that preladenant and SCH 412348 are potent and selective A 2A receptor antagonists and provide further evidence of the potential therapeutic benefits of A 2A receptor inhibition in PD (with reduced risk of dyskinesias) and depression (one of the primary nonmotor symptoms of PD).Adenosine modulates neuronal function via its interaction with glutamatergic, cholinergic, GABAergic, and dopaminergic neurotransmitter systems (Kurokawa et al

Selective A2A adenosine receptor agonists are potent vasodilators that reduce blood pressure and induce marked increments in heart rate and plasma renin activity (PRA). To examine the mechanisms and pressor relevance of these cardiac and renin responses, we measured blood pressure and heart rate by telemetry and PRA in separate sets of spontaneously hypertensive rats (SHRs), which were given i.p. 2-hexynyl-5-methylcarboxamidoadenosine (2HE-NECA, 0.01 mg/kg) and 2-[4-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosin e (CGS 21680, 0.1 mg/kg) alone and after pretreatment with the beta 1-adrenoceptor blocking agent atenolol (100 mg/kg). The effects of 2HE-NECA (0.003 mg/kg) also were examined after pretreatment with the angiotensin-converting enzyme (ACE) inhibitor spirapril (3 mg/kg). Both A2A agonists induced marked reductions in blood pressure, associated with significant increments in heart rate and in PRA. Atenolol reduced blood pressure to the same extent as did the A2A agonists and markedly decreased heart rate and PRA. Pretreatment with atenolol entirely prevented the increase in heart rate and in PRA induced by the two A2A agonists but potentiated only slightly their antihypertensive effect. Spirapril alone reduced blood pressure and increased PRA and when given before 2HE-NECA potentiated its depressor and renin-stimulating effects by 44% and 69%, respectively. These results suggest that the increase in heart rate and in PRA induced by A2A agonists is the result of a reflex increase in sympathetic activity triggered by the decrease in blood pressure rather than of a direct stimulating effect on cardiac and renal A2A-adenosine receptors; the reactive activation of the renin-angiotensin system elicited by these compounds may contribute to blunting their antihypertensive effect.

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