Recent Patents on CNS Drug Discovery, 2007, 2, 1-21 1 1574-8898/07 $100.00+.00 © 2007 Bentham Science Publishers Ltd. Blocking Striatal Adenosine A 2A Receptors: A New Strategy for Basal Ganglia Disorders Christa E. Müller 1 and Sergi Ferré 2, * 1 Pharmaceutical Institute, University of Bonn, Germany, and 2 National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA Received: October 12, 2006; Accepted: November 17, 2006; Revised: November 28, 2006 Abstract: Adenosine A 2A receptors are highly concentrated in the striatum, where they play an important modulatory role of glutamatergic transmission to the GABAergic enkephalinergic neuron, which function is particularly compromised in Parkinson’s disease and in the early stages of Huntington’s disease. An important amount of preclinical data suggested the possible application of A 2A receptor antagonists in Parkinson’s disease, particularly as adjuvant therapy to the currently used dopaminergic agonists. Several A 2A receptor antagonists are currently in clinical trials in patients with Parkinson’s disease and initial results have been promising. In recent years, many pharmaceutical companies have started programs to develop A 2A antagonists for Parkinson’s disease and for other indications, such as neurodegenerative diseases in general, depression and restless legs syndrome. Antagonists with high A 2A receptor affinity and selectivity have been developed from various chemical classes of compounds, including xanthines, adenines and other amino-substituted heterocyclic compounds. Novel structures include benzothiazole and thiazolopyridine derivatives. The present review describes properties of standard A 2A receptor antagonists including those in clinical development. Furthermore, the different chemical classes of A 2A receptor antagonists that have been described in the literature, including recent patent literature, will be presented. Keywords: Adenosine, xanthines, adenine derivative, adenine analog, Parkinson’s disease, adenosine receptor, antagonist, istradefylline, A 2A receptor, pharmacophore model. STRIATAL DYSFUNCTION IN MOVEMENT DISORDERS The striatum is the main input and information process- ing structure of the basal ganglia. Cortico-limbic-thalamic glutamatergic and mesencephalic dopaminergic systems converge in the GABAergic medium-sized spiny neurons, which constitute more than 90% of the striatal neuronal population [1]. These are efferent neurons which can be classified into two major classes according to their peptide expression: GABAergic enkephalinergic and GABAergic dynorphinergic neurons [1]. GABAergic enkephalinergic neurons express dopamine and adenosine receptors predominantly of the A 2A and D 2 subtype, respectively, while GABAergic dynorphinergic neurons express dopamine and adenosine receptors predominantly of the A 1 and D 1 subtype, respectively [1-3]. In addition, there are different types of GABAergic interneurons (parvalbumin, calretinin or soma- tostatin internerons) and large cholinergic interneurons [4]. The striatum is functionally subdivided in dorsal and ventral striatum. The dorsal striatum (mostly represented by the nucleus caudate-putamen) is involved in the performance and learning of complex motor acts. The dorsal striatum receives glutamatergic input from sensoriomotor and association cortical areas and dopaminergic input from the substantia nigra pars compacta [1,5] (Fig. 1). The ventral striatum (mostly represented by the nucleus accumbens) forms part of brain circuits involved in goal-directed *Address correspondence to this author at the National Institute on Drug Abuse, I.R.P., N.I.H., D.H.H.S., 5500 Nathan Shock Drive, Baltimore, MD 21224, USA; E-mail: sferre@intra.nida.nih.gov behaviours, in the conversion of motivation into action, into the selection of appropriate behavioral responses elicited by specific motivational stimuli. Different from the dorsal striatum, the ventral striatum (mostly represented by the nucleus accumbens) receives glutamatergic input from limbic and paralimbic cortices, as well as from the amygdala and hippocampus, and dopaminergic input from the ventral tegmental area [1,5]. In the dorsal part of the striatum the two subtypes of striatal GABAergic efferent neurons give rise to the two dorsal striatal efferent systems, which connect the dorsal striatum with the output structures of the basal ganglia, the substantia nigra pars reticulata and the internal segment of the globus pallidus (GPi; entopeduncular nucleus in rodents) [1] (Fig. 1). These are called “direct” and “indirect” pathways. The direct pathway is made of GABAergic dynorphinergic neurons, which directly connect the striatum with the output structures. The indirect pathway consists of GABAergic enkephalinergic neurons, which connect the striatum with the external segment of the globus pallidus (GPe; globus pallidus in rodents), GABAergic neurons which connect the GPe with the subthalamic nucleus (STN) and glutamatergic neurons which connect the STN with the output structures. GPe GABAergic neurons also project directly to the output structures without using the STN relay [1] (Fig. 1). Stimulation of the direct pathway results in motor activation and stimulation of the indirect pathway produces motor inhibition. Penney and Young [6] suggested that the striato-GPe-STN circuit might be involved in the suppression of unwanted motor responses. Dopamine, or dopamine agonists, will induce motor activation by activating the direct pathway (acting on stimulatory D 1 receptors localized in GABAergic dynorphinergic neurons)