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-(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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Directed screening of compounds selected from the Glaxo registry file for contractile activity on the isolated guinea pig gallbladder (GPGB) identified a series of 1,5-benzodiazepines with peripheral cholecystokinin (CCK) receptor agonist activity. Agonist efficacy within this series was modulated by variation of substituents on the N1-anilinoacetamide moiety. Remarkably, a single methyl group confers agonist activity, with an N-isopropyl substituent providing optimal efficacy. Hydrophilic substituents on the anilino nitrogen abolish agonist activity or produce antagonists of CCK. In contrast, hydrophilic electron-donating groups at the para-position of the anilino ring enhance or maintain in vitro and in vivo agonist activity. Despite decreased affinity for the human CCK-A receptor, relative to CCK-8, some of these compounds are equipotent to CCK as anorectic agents in rats following intraperitoneal administration.