International Conference on Medicinal and Pharmaceutical Chemistry
December 5-7, 2016 | Dubai, UAE
The dual-acting AChEInhibitor and H3 receptor antagonist UW-MD-72 reverses amnesia induced byscopolamine or dizocilpinein passive avoidance paradigm in rats
1College of Medicine & Health Sciences, United Arab Emirates University, United Arab Emirates
2Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, Germany
3Institute of Pharmacy and Food Chemistry, Julius-Maximilian University of Würzburg, Germany
Both the acetylcholine esterase (AChE) and the histamine H3 receptor (H3R) are involved in the metabolism and modulation of acetylcholine release and numerous other centrally acting neurotransmitters. Hence, dual-active AChE inhibitors (AChEIs) and H3 R antagonists hold potential to treat cognitive disorders like Alzheimerʼs disease (AD). The novel dual-acting AChEI and H3 R antagonistUW-MD-72 shows excellent selectivity profiles over the AChEʼsisoenzymebutyrylcholinesterase (BChE) as well as high and balanced in vitro affinities at both AChE and hH3R with IC50 of 5.4 µM on hAChEand hH3R antagonism with Ki of 2.54 µM, respectively. In the current study, the effects of UW-MD-72 (1.25, 2.5, and 5 mg/kg, i.p.) on memory deficits induced by scopolamine (SCO) and dizocilpine (DIZ) were investigatedin a step-through type passive avoidance paradigm in adult male rats applying donepezil (DOZ) and pitolisant (PIT) as reference drugs. The results show that acute systemic administration of UW-MD-72 significantly ameliorated the SCO- and DIZ-induced amnesic effects. Furthermore, the ameliorating activity of UW-MD-72in DIZ-induced amnesia was partly reversed when rats were pretreated with zolantidine, but not with the H1R antagonist pyrilamine. Moreover, ameliorative effect of UW-MD-72 in DIZ-induced amnesia was strongly reversed when rats were pretreated with a combination of ZOL and SCO, indicating that these memory enhancing effects were partly observed through histaminergic H2R as well as muscarinic cholinergic neurotransmission. These results demonstrate the ameliorative effects of UW-MD-72 in two in-vivo memory models and provide evidence for the potential of dual-acting AChEI and H3 R antagonists to treat cognitive disorders.
Dr Bassem Sadek is Associate Professor of Pharmacology in College of Medicine and Health Sciences, UAEUniversity. He received his B. Pharm. in 1994 from The Free University of Berlin (FUB), Germany, and PhD in Medicinal Chemistry, Drug Design and Development in 1999 from FUB University (Germany). Over the years, he has developed innovative research projects which focused on the identification and manipulation of brain signaling regulating psychiatric as well as neurodegenerative disorders such as Alzheimer, addiction, depression, epilepsy, anxiety, and stress. Dr Sadek is a member of editorial board and a peer-reviewer to many international journals.