title: 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.
abstract: 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 5.4μM on hAChE and hH3R antagonism with Ki of 2.54μM, respectively. In the current study, the effects of UW-MD-72 (1.25, 2.5, and 5mg/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 (2mg/kg, i.p.) and DIZ (0.1mg/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 (1.25mg/kg, i.p.) in DIZ-induced amnesia was partly reversed when rats were pretreated with the centrally-acting H2R antagonist zolantidine (ZOL, 10mg/kg, i.p.), but not with the CNS penetrant H1R antagonist pyrilamine (PYR, 10mg/kg, i.p.). Moreover, ameliorative effect of UW-MD-72 (1.25mg/kg, i.p.) in DIZ-induced amnesia was strongly reversed when rats were pretreated with a combination of ZOL (10mg/kg, i.p.) and SCO (1.0mg/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.
authors: Department of Pharmacology and Therapeutics, College of Medicine & Health Sciences, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates. Electronic address: bassem.sadek@uaeu.ac.ae.
authors: Bassem
authors: B
authors: Sadek
authors: Department of Pharmacology and Therapeutics, College of Medicine & Health Sciences, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates.
authors: Nadia
authors: N
authors: Khan
authors: Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors: Fouad H
authors: FH
authors: Darras
authors: Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors: Steffen
authors: S
authors: Pockes
authors: Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany; Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, Julius-Maximilian University of Würzburg, Am Hubland, D-97074 Würzburg, Germany.
authors: Michael
authors: M
authors: Decker
mesh_terms: D000647:Amnesia / Q000139:chemically induced / Q000188:drug therapy*; D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects*; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity; D054828:Histamine H3 Antagonists / Q000627:therapeutic use*; D008297:Male; D011758:Pyrroles / Q000737:chemistry / Q000627:therapeutic use*; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use; D011799:Quinazolines / Q000737:chemistry / Q000627:therapeutic use*; D052999:Quinazolinones / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D012601:Scopolamine / Q000633:toxicity*
chemical_list: C000610770:7-(3-(piperidin-1-yl)propoxy)-1,2,3,9-tetrahydropyrrolo(2,1-b)quinazoline; D002800:Cholinesterase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D054828:Histamine H3 Antagonists; D011758:Pyrroles; D011759:Pyrrolidines; D011799:Quinazolines; D052999:Quinazolinones; C000621154:UW-MD-72 compound; D016291:Dizocilpine Maleate; D012601:Scopolamine
keywords: Acetylcholinesterase; Dizocilpine; Dual-acting ligand; Histamine H(3) receptor; Learning; Memory; Passive avoidance paradigm; Pyrilamine; Scopolamine; Zolantidine