A2 adenosine receptors: their presence and neuromodulatory role in the central nervous system (original) (raw)

1996, General Pharmacology: The Vascular System

Adenosine is an endogenous neuromodulator that exerts its depressant effect on neurons by acting on the A, adenosine receptor subtype. Excitatory actions of adenosine, mediated by the activation of the Az adenosine receptor subtype, have also been shown in the central nervous system. 2. Adenosine Az, receptors are highly localized in the striatum, as demonstrated by the binding assay of the Aza selective agonist, CGS2680, and by analysis of the A2 receptor mRNA localization with in situ hybridization histochemistry. However, adenosine Az, receptors, albeit at lower levels, are also localized in other brain regions, such as the cortex and the hippocampus. 3. In the striatum, adenosine A2, receptors are implicated in the control of motor activity. Evidences exists of an antagonistic interaction between adenosine A2, and dopamine Dz receptors. 4. Utilizing selective agonists and antagonists for adenosine Az, receptors, their role in the modulation of the release of several neurotransmitters (acetylcholine, dopamine, glutamate, GABA) has been extensively studied in the brain (striatum, cortex, hippocampus). Controversial results have been obtained and, because the overall effect of endogenous adenosine in the brain is that of an inhibitory tonus, the physiological meaning of the excitatory A2 receptor remains to be clarified. GEN PHARMAC 27;6:925-933, 1996 KEY WORDS. Adenosine, central nervous system, S. Latini et al. (2-CADO)>N-ethylcarboxamidoadenosine (NECA) > S-PIA > 2-(phenylamino)adenosine (CV1808), and for the A2 receptor is: 2-[[2-[4-(2-carboxyethyl)phenyl]ethyl]amino]-N-ethylcarboxamidoadenosine (CGS21680) =NECA> 2-CADO>CV 1808 =R-PIA> CPA=CHA>S-PIA (Williams, 1990). Recently, new adenosine agonists, such as 2-chloro-N6-cyclopentyladenosine (CCPA), with high affinity (Ki=0.4 nM) and selectivity (about 10,000-fold) for A~ receptors (Lohse et al., 1988b), and 2-hexynyl-NECA with high affinity (/(,=3.8 nM) and selectivity for A2 vs AI receptors, on the order of 12-fold, have been described (Cristalli et al., 1992). Both classes of adenosine receptors can be antagonized by xanthine compounds, such as caffeine, theophylline and related 8-phenylxanthines. More recently, a number of selective xanthine antagonists, such as 8-cyclopenthyl-l,3-dipropylxanthine (DPCPX) for A~ receptors (Ki=0.5 nM; AdAl =700) (Bruns etal., 1987b; Lohse et al., 1987), (E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine (KF17837) (K,=I.0 nM; AI/A2=62) (Nonaka et al., 1994), and 8-(3-chlorostyryl)caffeine (CSC) (K=54 nM; AI/A:=518) (Jacobson et al., 1993) for A2 receptors, have been developed. Several non-xanthine antagonists selective for A2 receptors, but with low water solubility, such as 4-amino-8-chloro-1-phenyl[1,2,4]triazolo[4,3-e~]quinoxaline (CP66713) (K, = 12 nM; AI/A2 = 13.0) (Sarges eta/., 1990), and 9-chloro-2-(2-furanyl)-5,6-dihydro-1,2,4-triazolo[1,5-c]quinazoline-5-imine (CGS15943A) (K=4 nM; At/A2=6) (Jarvis et al., 1991), have also recently been described. These compounds are useful in the characterization of A~ and A2 receptor subtypes. A sub-classification of the A~ receptor into A~.~, with high affinity for agonists and located in the central nervous system, and A~b, with low affinity and located in the peripheral nervous system, has been proposed (Gustafsson et al., 1990). However, there is currently no evidence at the molecular level to support the existence of A~, and A,~ receptors. A~ receptors have also been subclassified into A2,, a high-affinity receptor highly localized in the striatum, and A21~, a low-affinity receptor that exists in ahnost all areas of the brain (Bruns et al., 1986). Compounds such as CV1808 and CGS21680 have been developed that show high affinity for the rat striatal A,,, receptor (Bruns et al., 1986; Jarvis et al., 1989b), and could be used to differentiate A:, from either A> or A~ receptors. Adenosine A2~, and A2b receptors have also been cloned from several animal species (Linden et al., 1994). Recently, another adenosine receptor, termed A~, has been cloned in the rat brain (Zhou et al., 1992). Although this name was previously used by Ribeiro and Sebastiao (1986) to indicate a presynaptic adenosine receptor at the neuromuscular junction of the frog sartorius muscle, there seems to be no relationship between this and the cloned receptor. An adenosine receptor, termed A4, has been characterized in rat brain tissue using CV1808 (Cornfield et al., 1992), but it has not yet been cloned. Thus, the original AI and A., receptor classification has been extended, because to date 4 distinct adenosine receptors (AI, A~,~,, A2b, A~) have been cloned from a variety of mammalian species (see Table 1). LOCALIZATION OF ADENOSINE Az RECEPTORS IN THE BRAIN The distribution of adenosine receptor subtypes in the mammalian brain has been extensively studied (Goodman and Snyder, 1982; Jarvis, 1988). Adenosine A1 receptors have been well characterized by using binding assays (