**5. Active drugs on adenosine receptors and their clinical applications**

Nowadays there is increasing interest in the therapeutic potential of adenosinergic compounds (including receptor agonists and antagonists, enzyme inhibitors and others), and many adenosine compounds have been evaluated.

#### **5.1 Adenosine receptor ligands and their potential as novel drugs**

Adenosine itself, for a long time, was the only adenosine agonist used in humans. It is widely used in the treatment of paroxysmal supraventricular tachycardia (Adenocard®) due to its activation of A1R, and as a diagnostic for myocardial perfusion imaging (Adenoscan®) utilizing its A2AR-activating effects resulting in vasodilation (Müller & Jacobson, 2011). However, other A1R-selective agonists such as Selodenoson, Capadenoson e Tecadenoson have been clinically evaluated for the treatment of paroxysmal supraventricular tachycardia, atrial fibrillation, or angina pectoris (Müller & Jacobson, 2011). Still talking about cardiovascular disorders, selective A2AR agonist, Apadenoson, Binodenoson and Sonedenoson appears as candidates for clinical use (Awad et al., 2006; Desai et al., 2005; Udelson et al. 2004). These agonists are of interest as vasodilator agents in cardiac imaging (Cerqueira, 2006) and inflammation suppressors. Accordingly, Regadenoson is already approved for diagnostic imaging (Iskandrian et al., 2007). A3R selective agonists are also currently in clinical trials and exhibit nanomolar affinity at the receptor, CF101 (Can-Fite Biopharma) and Cl-IB-MECA (CF102) are in trials for autoimmune inflammatory disorders

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distinct kinds of pain reaching clinical trials in the next years is clear.

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and for liver cancer, respectively. Two other A3R agonists CP-608,039 and its N6-(2,5 dichlorobenzyl) analogue CP-532,903 were previously under development for cardioprotection. MRS3558 (CF502) is in preclinical development for the treatment of autoimmune disease (Avni et al., 2010; Wan et al., 2008).

#### **5.2 Adenosinergic drugs in pain clinical studies and practical**

Clinical studies confirm the pre-clinical trials showing that in neuropathic pain patients, adenosine was able to alleviate spontaneous pain, tactile and thermal allodynia, as well as thermal hyperalgesia (Qu et al., 1997). In addition, intravenous infusion of adenosine during breast surgery reduced the postoperative pain (Lynch et al., 2003; Sollevi et al., 1995). Spinal administration of adenosine and adenosine analogs in humans also exhibited analgesic effect. A phase I clinical safety study in healthy volunteers demonstrated that 1000 μg of adenosine given intrathecally lacked side effects and led to a significant decrease in mustard oil-induced inflammatory pain, in tourniquet induced ischemic pain, and decreased areas of secondary allodynia after skin inflammation (Rane et al., 1998).

In another study, a single dose of 0.1 – 0.5 mg/kg of SDZ WAG 994 (adenosine A1R agonist), was evaluated in a phase I clinical study, and this compound was well tolerated. A dose of 1 mg/kg was used in a randomized double-blind clinical trial to determine its efficacy in postoperative dental pain after third molar surgery. However, SDZ WAG 994 did not show significant difference from placebo and was not effective in attenuating postoperative pain after third molar surgery. On the other hand, at higher doses, the compound showed dosedependent adverse events (Seymour et al., 1999; Wagner et al., 1995; Yan et al., 2003).

Another full high-affinity A1R agonists, GR79236X, was also evaluated in patients with dental pain after third molar extraction. Patients received a 15-min double-blind infusion containing 10 μg/kg of GR79236X, unfortunately, no evidence of efficacy of GR79236X was observed with this compound compared with placebo (Sneyd et al., 2007). Another A1R agonist GW493838 developed by GlaxoSmithKline, was evaluated in phase II clinical trials to determine its analgesic effect in patients with postherpetic neuralgia or peripheral nerve injury caused by trauma or surgery. However, further development of GW493838 has been discontinued (Nelsen et al., 2004; as cited in Elzein & Zablocki, 2008).

Allosteric modulation of A1R function may also be an interesting tool. Accordingly, the A1Rselective allosteric enhancer T-62, given orally was also shown to reduce hypersensitivity in carrageenan-inflamed rats, in addition, phase I clinical trials of T62 have been completed as a treatment for neuropathic pain (Childers et al., 2005). Therewithal, the A2AR agonist BVT.115959 from Biovitrum completed the clinical trials for diabetic neuropathic pain and it was well tolerated but did not significantly improve pain symptoms (Biovitrum, 2005; Zylka, 2011).

## **6. Conclusion and future directions**

This chapter presented a general and updated review about the purinergic system with emphasis in adenosine receptors (P1) and pain. It is possible to conclude that the modulation of this system and its receptors is quite important and interesting for the control of pain. Recent studies have approached this system in new ways and contributed to the development of this research field. Some clinical studies have been carried out with purinergic drugs (adenosine analogs) and some studies have showed quite satisfactory effects, although others haven`t showed statistical difference between treated and nontreated groups. Finally, the possibility of new drugs targeting the purinergic system to treat distinct kinds of pain reaching clinical trials in the next years is clear.
