Dinucleoside polyphosphates act as agonists on purinergic P2Y receptors to mediate a variety of cellular processes. Symmetrical, naturally occurring purine dinucleotides are found in most living cells and their actions are generally known. Unsymmetrical purine dinucleotides and all pyrimidine containing dinucleotides, however, are not as common and therefore their actions are not well understood. To carry out a thorough examination of the activities and specificities of these dinucleotides, a robust method of synthesis was developed to allow manipulation of either nucleoside of the dinucleotide as well as the phosphate chain lengths. Adenosine containing dinucleotides exhibit some level of activity on P2Y 1 while uridine containing dinucleotides have some level of agonist response on P2Y 2 and P2Y 6 . The length of the linking phosphate chain determines a different specificity; diphosphates are most accurately mimicked by dinucleoside triphosphates and triphosphates most resemble dinucleoside tetraphosphates. The pharmacological activities and relative metabolic stabilities of these dinucleotides are reported with their potential therapeutic applications being discussed.

-(2Ј-deoxycytidine 5Ј)tetraphosphate, tetrasodium salt] is a deoxycytidine-uridine dinucleotide with agonist activity at the P2Y 2 receptor. In primate lung tissues, the P2Y 2 receptor mRNA was located by in situ hybridization predominantly in epithelial cells and not in smooth muscle or stromal tissue. The pharmacologic profile of INS37217 parallels that of UTP, leading to increased chloride and water secretion, increased cilia beat frequency, and increased mucin release. The combined effect of these actions was confirmed in an animal model of tracheal mucus velocity that showed that a single administration of INS37217 significantly enhanced mucus transport for at least 8 h after dosing. This extended duration of action is consistent with the ability of INS37217 to resist metabolism by airway cells and sputum enzymes. The enhanced metabolic stability and resultant increased duration of improved mucociliary clearance may confer significant advantages to INS37217 over other P2Y 2 agonists in the treatment of diseases such as cystic fibrosis.Cystic fibrosis (CF) is a recessive genetic disease, characterized by pulmonary and reproductive tract dysfunctions, which affects more than 30,000 people in the United States . CF is caused by mutations in the CF transmembrane regulator (CFTR) gene, which encodes for an apical membrane epithelial protein that functions both as a cAMP-regulated chloride channel and a regulator of the epithelial sodium channel (Boucher, 1994). A defective CFTR leads to abnormal fluid and solute transport across epithelia, which contributes to the formation of viscous, dehydrated mucus in airways. The resulting mucostasis leads to progressive loss of ventilatory function and severe inflammatory responses to chronic bacterial infection (Mickle and Cutting, 1998). Most deaths of patients with CF occur as a consequence of pulmonary disease. Although improved treatment of lung disease has increased longevity, the median age for survival is still only 32 years, and patients have significant morbidity, including frequent hospitalizations, throughout their lives (Ramsey, 1996). Current therapies for CF include inhaled antibiotics, bronchodilators, mucolytics, and physiotherapy. Clearly, new therapeutic approaches are needed for the prevention and treatment of CF lung disease.An emerging therapeutic paradigm for the treatment of Article, publication date, and citation information can be found at

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Diquafosol tetrasodium was well tolerated and was superior to placebo (vehicle) in reducing corneal staining and in relieving certain patient symptoms. Diquafosol has a favorable risk/benefit profile in a broad spectrum of patients with dry eye disease and is a novel topical treatment of dry eye.

Rabbit conjunctival epithelium exhibits UTP-dependent Cl(-) secretion into the tears. We investigated whether fluid secretion also takes place. Short-circuit current (I(sc)) was 14.9 +/- 1.4 microA/cm(2) (n = 16). Four P2Y(2) purinergic receptor agonists [UTP and the novel compounds INS365, INS306, and INS440 (Inspire Pharmaceuticals)] added apically (10 microM) resulted in temporary (approximately 30 min) I(sc) increases (88%, 66%, 57%, and 28%, respectively; n = 4 each). Importantly, the conjunctiva transported fluid from serosa to mucosa at a rate of 6.5 +/- 0.7 microl x h(-1) x cm(-2) (range 2.1--15.3, n = 20). Fluid transport was stimulated by mucosal additions of 10 microM: 1) UTP, from 7.4 +/- 2.3 to 10.7 +/- 3.3 microl x h(-1) x cm(-2), n = 5; and 2) INS365, from 6.3 +/- 1.0 to 9.8 +/- 2.5 microl. h(-1) x cm(-2), n = 5. Fluid transport was abolished by 1 mM ouabain (n = 5) and was drastically inhibited by 300 microM quinidine (from 6.4 +/- 1.2 to 3.6 +/- 1.0 microl x h(-1) x cm(-2), n = 4). We conclude that this epithelium secretes fluid actively and that P2Y(2) agonists stimulate both Cl(-) and fluid secretions.