[11C]-SCH-442416 was designed and synthesized by scientists at the University of Milano-Bicocca with the intent of development as a PET imaging probe. [11C]-SCH-442416 demonstrates a selective high affinity as an antagonist of the A2A Adenosine Receptor with a Ki of 0.48 nM. [11C]-SCH-442416 has demonstrated the ability to cross the blood-brain barrier and has been used as an imaging agent in a number of animals studies and at least one clinical trial in healthy human volunteers. It should be noted that the non-radio labeled form of SCH-442416 has been investigated in rats for the treatment of addictive behaviors.

Evodenoson (ATL-313) is an agonist of adenosine A2A receptor. It exerts anti-inflammatory activity through activation of adenosine A2A receptors on CD4+ T cells and neutrophils. Evodenoson demonstrates efficacy in animal models of sepsis, myocardial infarction, allograft rejection and enteritis.

Trabodenoson is a potent (Ki = 0.97 nM) and selective (>10,000- fold vs. adenosine 2 receptor) adenosine 1 receptor agonist. Ex vivo, trabodenoson (100 nM to 3 uM) progressively prolonged A-V-nodal conduction without reducing left ventricular function or coronary resistance. In vivo, trabodenoson up to a dose of 50 ug/kg did not reduce the carotid arterial blood pressure. Twice-daily ocular doses of trabodenoson, from 50 to 500 ug, were well tolerated and showed a dose-related decrease in intraocular pressure that was statistically significant and clinically relevant at 500 ug in patients with ocular hypertension or primary open-angle glaucoma. Trabodenoson had been in phase III clinical trial for the treatment of glaucoma and ocular hypertension. However, this development was discontinued.

Dexniguldipine (B8509-035, (-)-(R)-niguldipine) is a new dihydropyridine derivative, that exerts selective antiproliferative activity in a variety of tumor models and, in addition, has a high potency in overcoming multidrug resistance. Dexniguldipine is ( - )-(R)-enantiomer of niguldipine, of which the ( )-(S)-enantiomer shows pronounced cardiovascular hypotensive activity due to its high affinity for the voltage-dependent Ca2 channel. As compared with the (S)-enantiomer, the (R)-enantiomer has a 40-fold lower affinity for the Ca 2 channel and, accordingly, only minimal hypotensive activity in animal pharmacology models. Dexniguldipine have shown antiproliferative activity in several tumor cell lines, but the concentrations necessary to inhibit growth have varied by several orders of magnitude between cell lines. Initial results of preclinical investigations for the evaluation of the mechanism of its antiproliferative activity demonstrate that dexniguldipine interferes with intracellular signal transduction by affecting phosphoinositol pathways, protein kinase C expression, and intracellular Ca 2 metabolism. In a series of human tumor xenografts in vitro, dexniguldipine demonstrated selective antiproliferative activity against several tumor types, e.g., melanoma and renal-cell carcinoma. Striking results were obtained in a hamster model, in which neuroendocrine lung tumors could be completely eradicated by 20 weeks of oral treatment with 32.5mg/kg dexniguldipine, whereas Clara-cell-type lung tumors were not affected. In in vitro studies, dexniguldipine has been found to bind to P-glycoprotein (P-gp) and to enhance the cytotoxicity of chemotherapeutic agents such as doxorubicin and etoposide in several cell lines The synergistic effect may well be associated with the reversal of multidrug resistance (MDR) related to the activity of P-gp. In the clinical therapy of cancer, resistance to many cytostatic drugs is a major cause of treatment failure. However, the high potency of dexniguldipine (about 10-fold as compared with that of verapamil in vitro) and its low cardiovascular activity provide the opportunity to achieve blood or tumor concentrations that might be high enough to overcome Mdr 1 resistance in patients without producing dose-limiting cardiovascular effects.

Tozadenant (SYN115) is an adenosine A2A receptor antagonist initially developed for treatment of Parkinson's disease but may also have utility in other CNS disorders. A2a receptors are expressed in high concentration in the striatum of the brain and play an important role in regulating motor function. Tozadenant blocks the effect of endogenous adenosine at the A2a receptors, resulting in the potentiation of the effect of dopamine at the D2 receptor and inhibition of the effect of glutamate at the mGluR5 receptor. This enables restoration of motor function in Parkinson’s disease. Tozadenant has the potential for use as mono-therapy or adjunctive therapy in combination with L-Dopa and dopamine agonists for the treatment of the motor and non-motor symptoms associated with Parkinson’s disease. may also have neuroprotective effects, which raises the possibility that it could slow the deterioration of dopamine producing cells and modify disease progression. As was reported in international, multicentre, phase 2b, randomised, double-blind, placebo-controlled, parallel-group, dose-finding clinical trial of tozadenant in levodopa-treated patients with Parkinson's disease who had motor fluctuations tozadenant at 120 or 180 mg twice daily was generally well tolerated and was effective at reducing off-time.

8-chloroadenosine (8-Cl-Ado) is a ribonucleoside analog. The mechanism of its action remains poorly understood, however, it is known that the drug inhibits RNA synthesis. It has significant cytotoxic activity against lymphoid and myeloid malignant cells. The nucleoside analog 8-Cl-Ado is phosphorylated into its cytotoxic triphosphate 8-Cl-ATP. The accumulation of the cytotoxic metabolite results in a parallel decrease of the ATP cellular pools. 8-Cl-Ado gets incorporated into RNA during transcription, hindering this process. In addition, this triphosphate inhibits ATP-dependent poly(A) tail synthesis, and, as a consequence, mRNA processing is inhibited, resulting in vitro cytotoxicity in several solid and hematological malignancies. This agent is currently in clinical trials for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia.

CF102 known as Cl-IB-MECA (2-chloro-N6-(3-iodobenzyl)-adenosine-5’- N-methyl-uronamide), is a highly specific and selective agonist at the A3 adenosine receptor. Phase I/II study in hepatocellular carcinoma (HCC) successfully met its primary and secondary endpoints demonstrating initial indications for efficacy of CF102. A global Phase II study treating patients with CF102 as a second line therapy will start enroling patients shortly.

7-Methylxanthine is a methyl derivative of xanthine, found occasionally in human urine. 7-Methylxanthine is one of the purine components in urinary calculi. 7-methylxanthine (7-MX) is a metabolite of caffeine and theobromine, and has been shown to have low toxicity and no carcinogenic effects. 7-MX is known as a non-selective adenosine antagonist and has been shown to work against myopia. 7-MX has little effect on the proliferation or apoptosis of human RPE cells; however, 7-MX disturbs the proportion of cells in the G1 stage and inhibits the expression of ADORA1, ADORA2A, and ADORA2B in short-term treatment. 7-MX has been confirmed to reduce the severity of myopia and eye elongation induced by forming deprivation in guinea pigs and to counteract the thinning of the posterior sclera and of collagen fibrils induced by form deprivation. A clinical trial showed that 7-MX reduced eye elongation and myopia progression in childhood myopia.