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Your search keyword '"Nimczick, Martin"' showing total 10 results
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9. Aminobenzimidazoles and Structural Isomers as Templates for Dual-Acting Butyrylcholinesterase Inhibitors and hCB2 R Ligands To Combat Neurodegenerative Disorders.

Author

Dolles D, Nimczick M, Scheiner M, Ramler J, Stadtmüller P, Sawatzky E, Drakopoulos A, Sotriffer C, Wittmann HJ, Strasser A, and Decker M

Subjects
Amino Acid Sequence, Benzimidazoles metabolism, Benzimidazoles therapeutic use, Binding Sites, Butyrylcholinesterase metabolism, Cholinesterase Inhibitors chemical synthesis, Cholinesterase Inhibitors metabolism, Drug Design, Humans, Ligands, Molecular Docking Simulation, Molecular Dynamics Simulation, Molecular Sequence Data, Protein Structure, Tertiary, Receptor, Cannabinoid, CB1 chemistry, Receptor, Cannabinoid, CB1 metabolism, Receptor, Cannabinoid, CB2 metabolism, Sequence Alignment, Stereoisomerism, Structure-Activity Relationship, Benzimidazoles chemistry, Butyrylcholinesterase chemistry, Cholinesterase Inhibitors therapeutic use, Neurodegenerative Diseases drug therapy, Receptor, Cannabinoid, CB2 antagonists & inhibitors
Abstract

A pharmacophore model for butyrylcholinesterase (BChE) inhibitors was applied to a human cannabinoid subtype 2 receptor (hCB2 R) agonist and verified it as a first-generation lead for respective dual-acting compounds. The design, synthesis, and pharmacological evaluation of various derivatives led to the identification of aminobenzimidazoles as second-generation leads with micro- or sub-micromolar activities at both targets and excellent selectivity over hCB1 and AChE, respectively. Computational studies of the first- and second-generation lead structures by applying molecular dynamics (MD) on the active hCB2 R model, along with docking and MD on hBChE, has enabled an explanation of their binding profiles at the protein levels and opened the way for further optimization. Dual-acting compounds with "balanced" affinities and excellent selectivities could be obtained that represent leads for treatment of both cognitive and pathophysiological impairment occurring in neurodegenerative disorders., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Published
2016
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10. Synthesis, biological evaluation, and computational studies of Tri- and tetracyclic nitrogen-bridgehead compounds as potent dual-acting AChE inhibitors and hH3 receptor antagonists.

Author

Darras FH, Pockes S, Huang G, Wehle S, Strasser A, Wittmann HJ, Nimczick M, Sotriffer CA, and Decker M

Subjects
Acetylcholinesterase metabolism, Binding Sites drug effects, Binding Sites genetics, Cholinesterase Inhibitors chemical synthesis, Cholinesterase Inhibitors metabolism, Cholinesterase Inhibitors pharmacology, GTP Phosphohydrolases metabolism, Histamine H3 Antagonists chemical synthesis, Histamine H3 Antagonists metabolism, Histamine H3 Antagonists pharmacology, Humans, Molecular Docking Simulation, Molecular Dynamics Simulation, Molecular Structure, Nitrogen Compounds chemical synthesis, Nitrogen Compounds pharmacokinetics, Radioligand Assay, Receptors, Histamine genetics, Receptors, Histamine metabolism, Receptors, Histamine H1 genetics, Receptors, Histamine H1 metabolism, Receptors, Histamine H2 genetics, Receptors, Histamine H2 metabolism, Receptors, Histamine H3 genetics, Receptors, Histamine H3 metabolism, Cholinesterase Inhibitors chemistry, Histamine H3 Antagonists chemistry, Nitrogen Compounds chemistry
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.

Published
2014
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