We recently identified ASP5736, (N-(diaminomethylene)-1-(3,5-difluoropyridin-4-yl)-4-fluoroisoquinoline-7-carboxamide (2E)-but-2-enedioate), a novel antagonist of 5-HT5A receptor, and here describe the in vitro and in vivo characterization of this compound. ASP5736 exhibited a high affinity for the human 5-HT5A receptor (Ki = 3.6 ± 0.66 nM) and antagonized 5-carboxamidotryptamine (5-CT)-induced Ca(2+) influx in human cells stably expressing the 5-HT5A receptor with approximately 200-fold selectivity over other receptors, including other 5-HT receptor subtypes, enzymes, and channels except human 5-HT2c receptor (Ki = 286.8 nM) and 5-HT7 receptor (Ki = 122.9 nM). Further, ASP5736 dose-dependently antagonized the 5-CT-induced decrease in cAMP levels in HEK293 cells stably expressing the 5-HT5A receptor. We then evaluated the effects of ASP5736 on cognitive impairments in several animal models of schizophrenia. Working memory deficit in MK-801-treated mice and visual learning deficit in neonatally phencyclidine (PCP)-treated mice were both ameliorated by ASP5736. In addition, ASP5736 also attenuated MK-801- and methamphetamine (MAP)-induced hyperactivity in mice without causing sedation, catalepsy, or plasma prolactin increase. The addition of olanzapine did not affect ASP5736-induced cognitive enhancement, and neither the sedative nor cataleptogenic effects of olanzapine were worsened by ASP5736. These results collectively suggest that ASP5736 is a novel and potent 5-HT5A receptor antagonist that not only ameliorates positive-like symptoms but also cognitive impairments in animal models of schizophrenia, without adverse effects. Present studies also indicate that ASP5736 holds potential to satisfy currently unmet medical needs for the treatment of schizophrenia by either mono-therapy or co-administered with commercially available antipsychotics.
ABSTRACT-Genetically diabetic db/db mice and their normoglycemic littermates (+/+ mice) were studied to determine plasma levels of glucose, glucagon and insulin and hepatic gluconeogenic enzyme ac tivities. Plasma glucose levels did not differ significantly between the 5-week-old db/db and + / + mice, but increased with age in the former until the animals were 16-week-old. Similar age-associated changes were observed in the activities of the gluconeogenic enzymes, glucose-6-phosphatase (G-6-Pase) and fructose-l,6 diphosphatase (F-1,6-DPase). While the plasma levels of insulin and glucagon that peaked at 7 weeks of age did not parallel the hyperglycemia, the plasma glucagon/insulin (G/I) ratio roughly paralleled the hyperglycemia. Analysis of individual values for the db/db mice revealed statistically significant (P<0.001) correlations between plasma glucose levels and hepatic G-6-Pace (r=0.78) or F-1, 6-DPase (r=0.74) activ ity. There were also significant correlations between the G/I ratio and plasma glucose levels (P<0.001, r=0.66), hepatic G-6-Pase (P<0.01, r=0.48) or F-1,6-DPase (P<0.01, r=0.57) activity. It is thus conclud ed that the relative predominance of glucagon over insulin action plays an important role in the age associated development of hyperglycemia in db/db mice. Glucagon presumably activates the hepatic gluconeogenic enzymes to enhance hepatic glucose output.Keywords: Diabetic (db/db) mouse, Glucagon/insulin ratio, Gluconeogenesis, Hyperglycemia Genetically diabetic (db/db) mouse was first described by Hummel et al. (1) as an animal model of NIDDM (non-insulin-dependent diabetes mellitus). Detailed stud ies from the same laboratory have later showed that hyperinsulinemia was the first detectable abnormality in the mice (2-4). Interestingly, the blood insulin levels which decrease with age appear to be inversely correlated with the blood glucose levels. On the other hand, we have recently demonstrated that insulin resistance occurred in db/db mice before the manifestation of hyperglycemia and remained constant during the course of developing hyperglycemia (5). We thus speculate that insulin resistance causes compensatory insulin release that causes age-associated insulin depletion and leads to development of hyperglycemia. Decreased glucose utilization due to in sufficient insulin release was considered to be an explana tion for the hyperglycemia in db/db mice.It has also been postulated that accelerated glucose production contributes to the hyperglycemia of db/db mice (6). The speculation was extended by Chan et al. (7), who showed that hepatic glycogenolytic and gluconeo genic enzyme activities increased in db/db mice. While glucagon enhances hepatic glucose production by stimulating gluconeogenesis and glycogenolysis, db/db mice are hyperglucagonemic (4, 8) presumably due to en hanced pancreatic glucagon release (9). These results sug gest that hyperglucagonemia which enhances hepatic glu cose production plays an important role in the develop ment of hyperglycemia in db/db mice.As described ...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.