title: Synthesis, biological evaluation, and computational studies of Tri- and tetracyclic nitrogen-bridgehead compounds as potent dual-acting AChE inhibitors and hH3 receptor antagonists.
abstract: Combination of AChE inhibiting and histamine H3 receptor antagonizing properties in a single molecule might show synergistic effects to improve cognitive deficits in Alzheimer's disease, since both pharmacological actions are able to enhance cholinergic neurotransmission in the cortex. However, whereas AChE inhibitors prevent hydrolysis of acetylcholine also peripherally, histamine H3 antagonists will raise acetylcholine levels mostly in the brain due to predominant occurrence of the receptor in the central nervous system. In this work, we designed and synthesized two novel classes of tri- and tetracyclic nitrogen-bridgehead compounds acting as dual AChE inhibitors and histamine H3 antagonists by combining the nitrogen-bridgehead moiety of novel AChE inhibitors with a second N-basic fragment based on the piperidinylpropoxy pharmacophore with different spacer lengths. Intensive structure-activity relationships (SARs) with regard to both biological targets led to compound 41 which showed balanced affinities as hAChE inhibitor with IC50 = 33.9 nM, and hH3R antagonism with Ki = 76.2 nM with greater than 200-fold selectivity over the other histamine receptor subtypes. Molecular docking studies were performed to explain the potent AChE inhibition of the target compounds and molecular dynamics studies to explain high affinity at the hH3R.
authors.affiliation: Lehrstuhl für Pharmazeutische und Medizinische Chemie I, Institut für Pharmazie, ‡Lehrstuhl für Pharmazeutische und Medizinische Chemie II, Institut für Pharmazie, Universität Regensburg , Universitätsstraße 31, D-93053 Regensburg, Germany.
authors.forename: Fouad H
authors.initials: FH
authors.lastname: Darras
authors.forename: Steffen
authors.initials: S
authors.lastname: Pockes
authors.forename: Guozheng
authors.initials: G
authors.lastname: Huang
authors.forename: Sarah
authors.initials: S
authors.lastname: Wehle
authors.forename: Andrea
authors.initials: A
authors.lastname: Strasser
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Wittmann
authors.forename: Martin
authors.initials: M
authors.lastname: Nimczick
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Sotriffer
authors.forename: Michael
authors.initials: M
authors.lastname: Decker
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D020558:GTP Phosphohydrolases / Q000378:metabolism; D054828:Histamine H3 Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D017672:Nitrogen Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011869:Radioligand Assay; D011968:Receptors, Histamine / Q000235:genetics / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000235:genetics / Q000378:metabolism; D011970:Receptors, Histamine H2 / Q000235:genetics / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000235:genetics / Q000378:metabolism
chemical_list: D002800:Cholinesterase Inhibitors; D054828:Histamine H3 Antagonists; D017672:Nitrogen Compounds; D011968:Receptors, Histamine; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D018100:Receptors, Histamine H3; D000110:Acetylcholinesterase; D020558:GTP Phosphohydrolases