Carbamoylcholine analogs as nicotinic acetylcholine receptor agonists—Structural modifications of 3-(dimethylamino)butyl dimethylcarbamate (DMABC)

Exploration of the molecular architecture of the orthosteric binding site in the α4β2 nicotinic acetylcholine receptor with analogs of 3-(dimethylamino)butyl dimethylcarbamate (DMABC) and 1-(pyridin-3-yl)-1,4-diazepane

“…Analogs of 4 with aryl ethers in the C3-position (17)(18)(19)(20)(21) were found to have decreased affinities relative to 4 and corresponding alkyl phenyl analogs with substituents of comparable size as evident by the 14-and 3-fold lower affinity (α4β2 nAChR) of 17 and 20 relative to 22 and 23. These data are in concordance with observations made from previous C-3 substituted analogs of 4 in which introduction of a hydroxymethyl group in the C-3 position led to a significantly larger decrease in nAChR binding affinity compared to 4, [31] whereas the binding affinity of the corresponding ethyl analog was much less affected. [41] These data are consistent with a high internal energy of 17 (~10 kJ/mol)…”

“…Introduction of larger hydrophobic substituents, including isopropyl or cyclohexyl, in this position induced a shift from nanomolar to micromolar affinity at the heteromeric nAChRs [33]. Introduction of the more planar cyclopropyl, 3-thiophenyl, and phenyl substituents also led to significant decreases in binding affinity compared to the parent compound, 4 [31]. However, overlay of the X-ray structures of 3 and 4 ( Figure 3B) suggested that even larger substituents in the C-3 position of 4 could protrude along the interfacial cleft basically without limitation to length of the substituents.…”

“…The existence of this interfacial pocket is also evident from co-crystal structures with MLA and from covalent trapping experiments with a maleimide analog of MLA in both α7 and α4β2 receptors [28,29], it is evident that the pocket is not an AChBP artifact. The alternative In previous studies, we have explored the medicinal chemistry of 3-(dimethylamino)butyl dimethylcarbamate (4, DMABC) and its desmethyl analog 5 [31][32][33], and 1-(pyridin-3-yl)-1,4-diazepane (6) [34] as potent nAChR agonists (Figure 1). …”

“…α4β2, α4β4, and α3β4 as previously described. [32] c Binding data from Jensen et al [41] d Binding data from Hansen et al [31] e Binding data from Rohde et al [36] …”

hChAT: A Tool for the Chemoenzymatic Generation of Potential Acetyl/Butyrylcholinesterase Inhibitors

“…[10] Due to the decrease in acetylcholine, acetylcholinesterase (AChE) and BChE inhibitors have become targets for AD drug development. [11][12][13] Analogues of acetylcholine with AChE inhibitory activity have been shown to be one of the most direct treatments for the suppression of neurodegenerative diseases, such as AD. Although the benefits of these agents are modest, three compounds, donepezil (Aricept, Eisai/ Pfizer), [14] rivastigmine (Exelon, Novartis), [15] and galantamine (Reminyl, Shire/Johnson & Johnson), are available as US FDA approved drugs (Figure 1).…”