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  • The effect of transformation of the linker

    2019-07-11

    The effect of transformation of the linker Y between the carboxylic FAK Inhibitor 14 residue and the phenyl moiety of 2b was also investigated, and is illustrated in Table 5. Analogs 2b, 16, and 17, possessing conformationally restricted carboxylic acid residues, tended to show stronger antagonist activity than analogs 15 and 18 which possess the more flexible carboxylic acid residues. Cytochrome P450 inhibition by the optimized compounds was also investigated. As a result, 2b and 16 were found to possess the most desired in vitro profiles, based on their antagonist activity and P450 inhibition.
    Experimental
    Biological assay method
    Introduction Prostaglandin (PG) receptors, expressed primarily on cell surface membrane, have been classified (Coleman et al., 1994) and their cDNA have been cloned from human and mouse (Narumiya et al., 1999, Breyer, 2001, Hata and Breyer, 2004). Expression of PG receptors and their subtypes has been studied at pharmacological, biochemical and molecular levels in tissues and cells of various organs including the eye (Narumiya et al., 1999, 2004; Burelout et al., 2004, Mita et al., 2002, Takahashi et al., 2003, Iwasaki et al., 2003, Bhattacherjee et al., 1996, Bhattacherjee et al., 1997, Bhattacherjee et al., 1999, Csukas et al., 1992, 1993; Liu et al., 1996, Mukhopadhyay et al., 1997, Mukhopadhyay et al., 1999). In recent years, with the availability of prostaglandin receptor knockout mice, linkage of a number of physiological actions of prostaglandins to specific receptors has been established (Sugimoto et al., 1997, Segi et al., 1998, Thomas et al., 1998, Ushikubi et al., 1998, Hizaki et al., 1999, Tilley et al., 1999). For example, febrile response to PGE2, IL-1α and lipopolysaccharides is mediated by EP3 receptors and FP receptors play an important role in luteolysis. EP4 receptors are required for remodeling of ductus arteriosus after birth. Furthermore, studies with EP receptor knockout and wild type mice revealed that mediators like PGs and cytokines not only act on their own but also interact with each other to release secondary mediators which amplify or limit inflammatory responses (Kassis et al., 1989, Shinomiya et al., 2001, Takahashi et al., 2002). In our recent studies with EP2 and EP4 receptor knockout mice, we have demonstrated that the disruption of the blood aqueous barrier after paracentesis, PGE2, RANTES and SDF-1 treatment are mediated by EP2 and EP4 receptors (Bhattacherjee et al., 2002, Biswas et al., 2004a, Biswas et al., 2006). Leukocyte infiltration in the aqueous humor in response to lipopolysaccharides, have also been found to be mediated by EP2 and EP4 receptors (Bhattacherjee et al., 2002, Biswas et al., 2004a, Biswas et al., 2006). In the present study, we have examined ocular inflammatory responses in EP1 receptor knockout mice and also studied the interplay between EP1, EP2 and EP4 receptors during ocular inflammatory events.
    Materials and methods
    Results
    Discussion The precise role of each of the EP receptor subtypes in the pathophysiology of the eye and other organs and their underlying mechanisms are poorly understood because of the interplay not only between EP receptors, but also between other chemical mediators. The recent availability of PG receptor knockout mice and highly selective EP receptor agonists and antagonists has led to the revelation of novel roles of EP receptors. These roles include association of EP1 receptors with experimentally induced breast cancer in rats, colon cancer in mice (Kawamori et al., 2001, Kawamori et al., 2005), maintenance of gastric mucosal integrity (Araki et al., 2000, Takeuchi et al., 2002), constriction of porcine cerebral arteries (Jadhav et al., 2004), peripheral nociception (Moriyama et al., 2005) and mechanical hyperalgesia (Nakayama et al., 2002.) The precise role of EP1 receptors in the pathophsiology of the eye is not known. There is only one publication describing the ocular hypotensive action of an EP1 receptors agonist (Bhattacherjee et al., 1999). The expression of this receptor subtype has been reported in human and mouse ocular tissues (Schlotzer-Schrehardt et al., 2002, Biswas et al., 2004a, Biswas et al., 2006). In the present study, we have demonstrated that in the EP1 receptor knockout mice, the magnitude of the disruption of the blood–aqueous barrier in response to EP receptor agonist, PGE2, and after paracentesis and LPS injection was significantly higher than that in wild type mice. These results suggest that EP1 receptors may have a direct counter-inflammatory or modulatory effect, or both, on other EP receptor subtypes. The observation that a highly selective EP1 receptor antagonist had a moderate effect on the blood–aqueous barrier response to butaprost (an EP2 receptor agonist), in the wild type mice and also that the butaprost response in the EP1 knockout mice was not enhanced suggested that EP1 receptors do not have a modulatory effect on EP2 receptors.