TY - JOUR
T1 - The dual-acting AChE inhibitor and H3 receptor antagonist UW-MD-72 reverses amnesia induced by scopolamine or dizocilpine in passive avoidance paradigm in rats
AU - Sadek, Bassem
AU - Khan, Nadia
AU - Darras, Fouad H.
AU - Pockes, Steffen
AU - Decker, Michael
N1 - Funding Information:
This work was kindly supported by grants ( 31M126 , 31M255 , 31R077 ) from the United Arab Emirates University (to BS). M. Decker gratefully acknowledges the German Research Foundation (DFG) for financial support (DFG DE 1546/6-1 and DE 1546/6-3 ) as well as the German Academic Exchange Service (DAAD) for awarding a Ph.D. scholarship to F. H. Darras. The authors gratefully thank Professor Katarzyna Kieć-Kononowiczc, Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University-Medical College, Kraków/Poland for kindly providing us with the H 3 R standard antagonist/inverse agonist pitolisant (PIT).
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/10/15
Y1 - 2016/10/15
N2 - 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 H3R antagonists hold potential to treat cognitive disorders like Alzheimer's disease (AD). The novel dual-acting AChEI and H3R antagonist 7-(3-(piperidin-1-yl)propoxy)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (UW-MD-72) shows excellent selectivity profiles over the AChE's isoenzyme butyrylcholinesterase (BChE) as well as high and balanced in-vitro affinities at both AChE and hH3R with IC50 of 5.4 μM on hAChE and 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 the muscarinic cholinergic antagonist scopolamine (SCO) and the non-competitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine (DIZ) were investigated in a step-through type passive avoidance paradigm in adult male rats applying donepezil (DOZ) and pitolisant (PIT) as reference drugs. The results observed show that SCO (2 mg/kg, i.p.) and DIZ (0.1 mg/kg, i.p.) significantly impaired learning and memory in rats. However, acute systemic administration of UW-MD-72 significantly ameliorated the SCO- and DIZ-induced amnesic effects. Furthermore, the ameliorating activity of UW-MD-72 (1.25 mg/kg, i.p.) in DIZ-induced amnesia was partly reversed when rats were pretreated with the centrally-acting H2R antagonist zolantidine (ZOL, 10 mg/kg, i.p.), but not with the CNS penetrant H1R antagonist pyrilamine (PYR, 10 mg/kg, i.p.). Moreover, ameliorative effect of UW-MD-72 (1.25 mg/kg, i.p.) in DIZ-induced amnesia was strongly reversed when rats were pretreated with a combination of ZOL (10 mg/kg, i.p.) and SCO (1.0 mg/kg, i.p.), indicating that these memory enhancing effects were, in addition to other neural circuits, 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 H3R antagonists to treat cognitive disorders.
AB - 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 H3R antagonists hold potential to treat cognitive disorders like Alzheimer's disease (AD). The novel dual-acting AChEI and H3R antagonist 7-(3-(piperidin-1-yl)propoxy)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (UW-MD-72) shows excellent selectivity profiles over the AChE's isoenzyme butyrylcholinesterase (BChE) as well as high and balanced in-vitro affinities at both AChE and hH3R with IC50 of 5.4 μM on hAChE and 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 the muscarinic cholinergic antagonist scopolamine (SCO) and the non-competitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine (DIZ) were investigated in a step-through type passive avoidance paradigm in adult male rats applying donepezil (DOZ) and pitolisant (PIT) as reference drugs. The results observed show that SCO (2 mg/kg, i.p.) and DIZ (0.1 mg/kg, i.p.) significantly impaired learning and memory in rats. However, acute systemic administration of UW-MD-72 significantly ameliorated the SCO- and DIZ-induced amnesic effects. Furthermore, the ameliorating activity of UW-MD-72 (1.25 mg/kg, i.p.) in DIZ-induced amnesia was partly reversed when rats were pretreated with the centrally-acting H2R antagonist zolantidine (ZOL, 10 mg/kg, i.p.), but not with the CNS penetrant H1R antagonist pyrilamine (PYR, 10 mg/kg, i.p.). Moreover, ameliorative effect of UW-MD-72 (1.25 mg/kg, i.p.) in DIZ-induced amnesia was strongly reversed when rats were pretreated with a combination of ZOL (10 mg/kg, i.p.) and SCO (1.0 mg/kg, i.p.), indicating that these memory enhancing effects were, in addition to other neural circuits, 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 H3R antagonists to treat cognitive disorders.
KW - Acetylcholinesterase
KW - Dizocilpine
KW - Dual-acting ligand
KW - Histamine H receptor
KW - Learning
KW - Memory
KW - Passive avoidance paradigm
KW - Pyrilamine
KW - Scopolamine
KW - Zolantidine
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U2 - 10.1016/j.physbeh.2016.08.022
DO - 10.1016/j.physbeh.2016.08.022
M3 - Article
C2 - 27568232
AN - SCOPUS:84983735533
SN - 0031-9384
VL - 165
SP - 383
EP - 391
JO - Physiology and Behavior
JF - Physiology and Behavior
ER -