title: The dual-acting H3 receptor antagonist and AChE inhibitor UW-MD-71 dose-dependently enhances memory retrieval and reverses dizocilpine-induced memory impairment in rats.
abstract: Both the histamine H3 receptor (H3R) and acetylcholine esterase (AChE) are involved in the regulation of release and metabolism of acetylcholine and several other central neurotransmitters. Therefore, dual-active H3R antagonists and AChE inhibitors (AChEIs) have shown in several studies to hold promise to treat cognitive disorders like Alzheimer's disease (AD). The novel dual-acting H3R antagonist and AChEI 7-(3-(piperidin-1-yl)propoxy)-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline (UW-MD-71) with excellent selectivity profiles over both the three other HRs as well as the AChE's isoenzyme butyrylcholinesterase (BChE) shows high and balanced in vitro affinities at both H3R and AChE with IC50 of 33.9nM and hH3R antagonism with Ki of 76.2nM, respectively. In the present study, the effects of UW-MD-71 (1.25-5mg/kg, i.p.) on acquisition, consolidation, and retrieval in a one-trial inhibitory avoidance task in male rats were investigated applying donepezil (DOZ) and pitolisant (PIT) as reference drugs. Furthermore, the effects of UW-MD-71 on memory deficits induced by the non-competitive N-methyl-d-aspartate (NMDA) antagonist dizocilpine (DIZ) were tested. Our results indicate that administration of UW-MD-71 before the test session dose-dependently increased performance and enhanced procognitive effect on retrieval. However neither pre- nor post-training acute systemic administration of UW-MD-71 facilitated acquisition or consolidation. More importantly, UW-MD-71 (2.5mg/kg, i.p.) ameliorated the DIZ-induced amnesic effects. Furthermore, the procognitive activity of UW-MD-71 in retrieval was completely reversed and partly abrogated in DIZ-induced amnesia when rats were pretreated with the centrally-acting H2R antagonist zolantidine (ZOL), but not with the CNS penetrant H1R antagonist pyrilamine (PYR). These results demonstrate the procognitive effects of UW-MD-71 in two in vivo memory models, and are to our knowledge the first demonstration in vivo that a potent dual-acting H3R antagonist and AChEI is effective in improving retrieval processes in the one-trial inhibitory avoidance task and provide evidence to such compounds to treat cognitive disorders.
authors.affiliation: Department of Pharmacology and Therapeutics, College of Medicine & Health Sciences, P.O. Box 17666, Al Ain 0097, United Arab Emirates University, United Arab Emirates.
authors.forename: Nadia
authors.initials: N
authors.lastname: Khan
authors.affiliation: Department of Pharmacology and Therapeutics, College of Medicine & Health Sciences, P.O. Box 17666, Al Ain 0097, United Arab Emirates University, United Arab Emirates.
authors.forename: Ali
authors.initials: A
authors.lastname: Saad
authors.affiliation: Department of Pharmacology and Therapeutics, College of Medicine & Health Sciences, P.O. Box 17666, Al Ain 0097, United Arab Emirates University, United Arab Emirates.
authors.forename: Syed M
authors.initials: SM
authors.lastname: Nurulain
authors.affiliation: Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors.forename: Fouad H
authors.initials: FH
authors.lastname: Darras
authors.affiliation: 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 Würzburg, Am Hubland, D-97074 Würzburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Decker
authors.affiliation: Department of Pharmacology and Therapeutics, College of Medicine & Health Sciences, P.O. Box 17666, Al Ain 0097, United Arab Emirates University, United Arab Emirates. Electronic address: bassem.sadek@uaeu.ac.ae.
authors.forename: Bassem
authors.initials: B
authors.lastname: Sadek
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D052160:Benzothiazoles / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D054828:Histamine H3 Antagonists / Q000494:pharmacology*; D007189:Indans / Q000494:pharmacology; D008297:Male; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D008569:Memory Disorders / Q000188:drug therapy* / Q000378:metabolism; D018697:Nootropic Agents / Q000494:pharmacology*; D050198:Phenoxypropanolamines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011738:Pyrilamine / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D011897:Random Allocation; D017208:Rats, Wistar; D018100:Receptors, Histamine H3 / Q000378:metabolism
chemical_list: C000610770:7-(3-(piperidin-1-yl)propoxy)-1,2,3,9-tetrahydropyrrolo(2,1-b)quinazoline; D052160:Benzothiazoles; D002800:Cholinesterase Inhibitors; D054828:Histamine H3 Antagonists; D007189:Indans; D018697:Nootropic Agents; D050198:Phenoxypropanolamines; D010880:Piperidines; D011758:Pyrroles; D011799:Quinazolines; D018100:Receptors, Histamine H3; C516975:pitolisant; D016291:Dizocilpine Maleate; D000077265:Donepezil; D011738:Pyrilamine; C055302:zolantidine
keywords: Acetylcholinesterase; Dual-acting ligand; Histamine H(3) receptor; Inhibitory avoidance test; Learning; Memory; Pyrilamine; Zolantidine.