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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

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

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

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;

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

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**29** 

*Turkiye* 

Beril Anilanmert

**Therapeutic Organometallic Compounds** 

Most drugs used today are purely organic compounds. Especially after the enormous success of the cisplatin (Fig 1) in tumor treatment, interest in metal complexes has grown (Allardyce & Dyson, 2006). Synthetic organometallic compounds are generally considered to be toxic or non-compatible with biological systems. Despite this perception, the medicinal properties of organometallic compounds, in particular organo-transition metal compounds, have been probed for a long time and in the last few years the area has grown considerably. Transition metals have an important place within medicinal biochemistry (Rafique et al, 2010). Transition metals represent the d block element which includes groups 3 - 12 on the periodic table. They have partially filled d-shells in any of their commonly occuring oxidation state. Metal complex or coordination compound is a structure consisting of a central metal atom, bonded to a surrounding array of ligands (molecules or anions), which donate electron pair to the metal. Research has shown significant progress in utilization of transition metal complexes as drugs to treat several human diseases like carcinomas, lymphomas, infection control, anti-inflammatory, diabetes, and neurological disorders. Transition metals exhibit different oxidation states and can interact with a number of negatively charged molecules. This activity of transition metals has started the development of metal-based drugs with promising pharmacological application and may offer unique

**2. Therapeutic applications of some old and new organometallic complexes** 

Various metal complexes have been tested in anticancer therapy (Meng et al, 2009). The development of metal complexes with platinum central atoms such as cisplatin or carboplatin had an enormous impact on current cancer chemotherapy (Fig 1, 2) (Ott & Gust, 2007). In particular, cisplatin has become one of the most widely used drugs and is highly effective in treating several cancers such as ovarian and testicular cancers (Meng et al, 2009).

**1. Introduction** 

therapeutic opportunities.

**and discoveries and ongoing studies** 

Fig. 1. Molecular structure of cisplatin.

*Istanbul University, Institute of Forensic Sciences,* 

