Novel Acetylcholine and Carbamoylcholine Analogues: Development of a Functionally Selective α₄β₂ Nicotinic Acetylcholine Receptor Agonist

Abstract

A series of carbamoylcholine and acetylcholine analogues were synthesized and characterized pharmacologically at neuronal nicotinic acetylcholine receptors (nAChRs). Several of the compounds displayed low nanomolar binding affinities to the alpha4beta2 nAChR and pronounced selectivity for this subtype over alpha3beta4, alpha4beta4, and alpha7 nAChRs. The high nAChR activity of carbamoylcholine analogue 5d was found to reside in its R-enantiomer, a characteristic most likely true for all other compounds in the series. Interestingly, the pronounced alpha4beta2 selectivities exhibited by some of the compounds in the binding assays translated into functional selectivity. Compound 5a was a fairly potent partial alpha4beta2 nAChR agonist with negligible activities at the alpha3beta4 and alpha7 subtypes, thus being one of the few truly functionally selective alpha4beta2 nAChR agonists published to date. Ligand-protein docking experiments using homology models of the amino-terminal domains of alpha4beta2 and alpha3beta4 nAChRs identified residues Val111(beta2)/Ile113(beta4), Phe119(beta2)/Gln121(beta4), and Thr155(alpha4)/Ser150(alpha3) as possible key determinants of the alpha4beta2/alpha3beta4-selectivity displayed by the analogues.

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

“…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). …”

“…b Receptor binding affinity values for α4β2 represented as K i (µM) with pK i ± SEM values shown in brackets, determined in a [ 3 H]epibatidine binding assay with HEK293 cells stably expressing rat α4β2 as previously described [32]. c Data from Ussing et al[35] d Data from Edink et al[27] e Binding isotherm did not reach plateau within the tested range.…”

“…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] …”

Conformationally restrained carbamoylcholine homologues. Synthesis, pharmacology at neuronal nicotinic acetylcholine receptors and biostructural considerations

“…In recent studies, we have developed a series of carbamoylcholine (CCh) homologues that act as functionally α 4 β 2 -selective agonists ( CCh homologues 1 and 2 exhibit high degree of selectivity for nicotinic over muscarinic receptors, and in addition 2-5 display a pronounced degree of selectivity towards β 2 -containing nAChRs subtypes [18][19][20]. Initially, these CCh homologues were thought to bind to the nAChRs in a linear conformation similar to that of ACh or CCh [15].…”

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).…”