“Receptors recognize a distinct chemical entity and translate information from that entity into a form that the cell can read to alter its state” (Kenakin et al., 1992). Even though the receptors are often pharmacologically defined on the basis of synthetic compounds, they are assumed to have developed to respond to endogenous molecules. Therefore, receptors are generally named on the basis of their natural ligands. Hence, it is appropriate to very briefly summarize the evidence that purine nucleotides and nucleosides are natural ligands for a wide class of receptors.

In a seminal paper, Drury and Szent-Gyorgyi (1929) showed that adenosine exerted a large number of biological effects, including bradycardia and vasodilation. A wider interest in the role of adenosine followed from the demonstration in 1963 that adenosine can be produced by the hypoxic heart. Two groups independently formulated the hypothesis that adenosine may be involved in the metabolic regulation of coronary blood flow (Berne, 1963; Gerlach et al., 1963). The observation by de Gubareff and Sleator (1965) that the actions of adenosine in heart tissue could be blocked by caffeine suggested the existence of an adenosine receptor. The potent cardiovascular effects of adenosine led to an interest in the synthesis of new adenosine analogs, and careful dose-response studies with a number of these drugs (Cobbin et al., 1974) strongly suggested the presence of a receptor for adenosine-like compounds. Sattin and Rall (1970) reported that adenosine increased cyclic AMP accumulation in slices of rodent brain and that this adenosine-induced second-messenger response was blocked by methylxanthines. Their findings suggested that adenosine receptors exist in the central nervous system. The essentially simultaneous findings by Mcilwain (1972), that such brain slices actually elaborate adenosine in concentrations that would be sufficient to elevate cyclic AMP, provided support that these putative receptors were physiologically occupied by adenosine. Thus, in the 1970s there was good evidence that there were receptors for adenosine at which methylxanthines acted as antagonists. Biochemical evidence for the existence of multiple adenosine receptors was subsequently provided by the demonstration that adenosine analogs increased cyclic AMP production in some preparations and decreased it in others. Because the relative agonist potency for a variety of adenosine analogs was different for these two types of effects, the presence of two classes of receptors, called A1 and A2 (van Calker et al., 1979) or Ri and Ra (Londos et al., 1980), was proposed. The A1/A2 nomenclature is now generally used.

The presence of receptors for ADP, particularly on blood platelets, was also recognized several decades ago. Studies of the factors in blood that induce platelet aggregation led to the identification of ADP as an active component present in red blood cell extracts (Gaarder et al., 1961). The evidence that ADP and adenosine (presumably A2) receptors exist on platelets was summarized by Haslam and Cusack (1981).

Four decades ago, ATP was shown to produce important cardiovascular effects (Green and Stoner, 1950) and to be released from sensory nerves (Holton and Holton, 1954; Holton, 1959), hinting at a role in neural transmission. In his landmark review of purinergic nerves, Burnstock (1972) postulated the existence of specific ATP receptors. Although evidence in support of this idea was not overwhelming at the time, many subsequent studies have supported the existence of receptors for extracellular ATP (Burnstock and Brown, 1981; Gordon, 1986; O’Connor et al., 1991). Similarly, the evidence is now compelling that ATP plays important physiological and/ or pathophysiological roles in a variety of biological systems, including that of a neurotransmitter in peripheral and central neurons. Finally, diadenosinetetraphosphate is a dinucleotide stored in synaptic vesicles and chromaffin granules (Flodgaard and Klenow, 1982; Rodriguez del Castillo et al., 1988) and released therefrom (Pintor et al., 1991a, 1992). The purine dinucleotide also binds with subnanomolar affinity to receptors (Pintor et al., 1991b, 1993) and exerts biological effects (Pintor et al., 1993), indicating that it is an endogenous purinoceptor ligand.

Thus, strong evidence for the presence of receptors for the endogenous ligands adenosine, ADP, ATP, and dia-denosinetetraphosphate had accumulated. This group of receptors is called the purinoceptors. If at some future time there is compelling evidence that UTP, or another pyrimidine nucleotide, is an endogenous ligand at receptors that respond poorly or not at all to ATP, then this terminology may need revision.

https://pharmrev.aspetjournals.org/content/pharmrev/46/2/143.full.pdf

Nomenclature and classification of purinoceptors

In the 10 years since our previous International Union of Basic and Clinical Pharmacology report on the nomenclature and classification of adenosine receptors, no developments have led to major changes in the recommendations. However, there have been so many other developments that an update is needed. The fact that the structure of one of the adenosine receptors has recently been solved has already led to new ways of in silico screening of ligands. The evidence that adenosine receptors can form homo- and heteromultimers has accumulated, but the functional significance of such complexes remains unclear. The availability of mice with genetic modification of all the adenosine receptors has led to a clarification of the functional roles of adenosine, and to excellent means to study the specificity of drugs. There are also interesting associations between disease and structural variants in one or more of the adenosine receptors. Several new selective agonists and antagonists have become available. They provide improved possibilities for receptor classification. There are also developments hinting at the usefulness of allosteric modulators. Many drugs targeting adenosine receptors are in clinical trials, but the established therapeutic use is still very limited.

https://pharmrev.aspetjournals.org/content/pharmrev/63/1/1.full.pdf

International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and Classification of Adenosine Receptors—An Update

Recent developments in adenosine receptor ligands and their potential as novel drugs

An efficient methodology for the synthesis of unsymmetrical biheteroaryl molecules has been developed via Pd(II)-catalyzed oxidative C−H/C−H cross-coupling of heteroarenes. An inversion in reactivity and selectivity has been achieved successfully to perform the desired heterocoupling. This process allows the heterocoupling of not only electron-rich N-containing heteroarenes (e.g., xanthines, azoles, and indolizines) but also electron-poor pyridine N-oxides with various thiophenes or furans.

Palladium(II)-catalyzed oxidative C-H/C-H cross-coupling of heteroarenes.

Pharmacology of adenosine A2A receptors

A series of substituted 8-styryl derivatives of 1,3,7-alkylxanthines was synthesized as potential A2-selective adenosine receptor antagonists, and the potency at rat brain A1- and A2-receptors was studied in radioligand binding experiments. At the xanthine 7-position, only small hydrophobic substituents were tolerated in receptor binding. 7-Methyl analogues were roughly 1 order of magnitude more selective for A2 versus A1 receptors than the corresponding 7-H analogues. 1,3-Dimethylxanthine derivatives tended to be more selective for A2-receptors than the corresponding 1,3-diallyl, diethyl, or dipropyl derivatives. Substitutions of the phenyl ring at the 3-(monosubstituted) and 3,5-(disubstituted) positions were favored. 1,3, 7-Trimethyl-8-(3-chlorostyryl)xanthine was a moderately potent (Ki vs [3H]CGS 21680 was 54 nM) and highly A2-selective (520-fold) adenosine antagonist. 1,3,7-Trimethyl-8-[(3-carboxy-1-oxopropyl)amino] styryl]xanthine was highly A2-selective (250-fold) and of enhanced water solubility (max 19 mM). 1,3-Dipropyl-7-methyl-8-(3,5-dimethoxystyryl) xanthine was a potent (Ki = 24 nM) and very A2-selective (110-fold) adenosine antagonist.

Andrew van Bergen

Papers

Structure-activity relationships of 8-styrylxanthines as A2-selective adenosine antagonists.