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. 2014 Mar 19;5(3):225-42.
doi: 10.1021/cn4002126. Epub 2014 Jan 14.

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

Fouad H Darras  1 , Steffen Pockes, Guozheng Huang, Sarah Wehle, Andrea Strasser, Hans-Joachim Wittmann, Martin Nimczick, Christoph A Sotriffer, Michael Decker
Affiliations

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

Fouad H Darras et al. ACS Chem Neurosci. .

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.

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Figures

Chart 1
Chart 1. Schematic Illustration of the Merging Design Methodology for Synthesizing Dual Acting AChE inhibitors/H3 Antagonist Hybrid Structures−
Chart 2
Chart 2. Previously Described Acetylcholinesterase Inhibitors/Histamine H3 Receptor Antagonists,−
Chart 3
Chart 3. Tri- and Tetracyclic Compounds As Starting Points for H3/AChE Dual Acting Compounds’ SARs
Scheme 1
Scheme 1. Synthesis of Tetracyclic N-Bridgehead Compounds
Reagents: (i) CH3I, N,N-diisopropylethylamine, N,N-dimethylacetamide, 40 °C, 24 h; (ii) toluene/reflux, 24 h; (iii) H2, Pd/C, ethanol, rt, 24 h; (iv) 1,3-dibromopropane or 1,6-dibromohexane, K2CO3, KI, acetonitrile, 90 °C, 3 h; (v) piperidine, morpholine, pyrrolidine, or azepane, K2CO3, KI, acetonitrile, 90 °C, 3 h; (vi) LiAlH4, THF, 70 °C, 3 h.
Scheme 2
Scheme 2. Synthesis of Tricyclic N-Bridgehead Compounds (quinazolinones and diamines)
Reagents: (i) MW, 200 W, 220 °C, 1 h; (ii) H2, Pd/C, ethanol, rt, 24 h; (iii) 1,3-dibromopropane or 1,6-dibromohexane, K2CO3, KI, acetonitrile, 90 °C, 3 h; (iv) pyrrolidine, piperidine, or azepane, K2CO3, KI, acetonitrile, 90 °C, 3 h; (v) LiAlH4, THF, 70 °C, 3 h.
Scheme 3
Scheme 3. Selective Reduction of Quinazolinone Imine Bond to the Corresponding Amine
Scheme 4
Scheme 4. Selective Reduction of Quinazolinones by Clemmensen Reduction
Figure 1
Figure 1
Lineweaver–Burk plot resulting from substrate–velocity curves of EeAChE activity with different substrate (ATC) concentrations (50–450 μM) in the presence of 1, 10, 50, 100, and 200 nM compound 41.
Figure 2
Figure 2
Binding assay results toward hH1R, hH2R, and hH4R, applying a 10 μM concentration of the most potent hH3R antagonist compounds. Diphenhydramine (DPH) as hH1R standard ligand and histamine (HIS) as hH2R, and hH4R standard ligand.
Figure 3
Figure 3
Functional assay (GTPase) results at the hH3 receptor applying a 10 μM concentration of all synthesized compounds with water as a baseline and thioperamide as control (antagonist).
Figure 4
Figure 4
(A) Docking pose showing the inverted binding mode of inhibitor 41 (cyan) with a 4.2 Å cation−π interaction to Trp86 and potential hydrogen bonds to a water molecule (3.2 Å) and Tyr72 (3.4 Å). Inhibitor 42 (green) shows the same placement of the piperidine ring near the CAS (4.2 Å to Trp86) and a distance of 4.3 Å to the Tyr341 backbone carbonyl. (B) Selected docking pose of the tetracyclic inhibitor 21 (pink, R-enantiomeric form) showing the inverted binding mode. The inhibitor is stabilized by a 3.0 Å interaction of the scaffold carbonyl oxygen with a water molecule and a 4.3 Å cation−π interaction of the piperidine with Trp86 near the CAS. Color code: red, conserved water molecules; gray, hAChE binding site; catalytic active site, Ser203, His447 (Glu334 not shown here); peripheral anionic site (PAS), Tyr72, Trp286. Both figures were created using Pymol.
Figure 5
Figure 5
Compound 41 embedded in the binding pocket of the inactive hH3R, obtained as a snapshot of MD simulation. The translucent surface of the ligand is colored according to the electrostatic potential.
Figure 6
Figure 6
(A) Time evolution of the distances between the hydrogen of the protonated piperidine of 41 and the oxygens of the Asp3.32 side chain during the 10 ns productive MD. (B) Time evolution of the distances between the hydrogen of the protonated amidine of 41 and the oxygens of the Glu5.46 side chain during the 10 ns productive MD.
Chart 4
Chart 4. FUB836 and Imoproxifan,
Figure 7
Figure 7
Comparison of selected amino acids, located in the binding pocket of the four human histamine receptor subtypes; green, highly conserved amino acids within all subtypes or identical amino acids between hH3R and hH4R, red: amino acids being different between hH3R and hH4R.
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