Novel nicotinic acetylcholine receptor agonists containing carbonyl moiety as a hydrogen bond acceptor

The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor ligands. Part 2: Carboxamide derivatives with different spacer motifs

“…An additional pharmacophoric point, a hydrogen bond acceptor (HBA) motif, is often introduced as a pyridine moiety and less often as carbonyl functionality or as heteroaryls. 6,7 The bulkiness of ring structures containing the potentially charged nitrogen and moieties attached to the HBA system influence both affinity and functionality. 8 The diazabicyclic scaffold 3,7-diazabicyclo[3.3.1]nonane (bispidine) originated from the natural product and nAChR ligand cytisine 1 (Fig.…”

“…It is a privileged scaffold and has been used for the development of nAChR compounds. 6,7,8–15 In our previous 3,7-diazabicyclo[3.3.1]nonane project, we explored the influence of different non-heteroaryl based HBA systems. 7 We also reported that 3,7-diazabicyclo[3.3.1]nonane is active on nAChRs and that some 3,7-diazabicyclo[3.3.1]nonane carboxamides showed selectivity for the α4β2* nAChR.…”

The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor (nAChR) ligands. Part 1: The influence of different hydrogen bond acceptor systems on alkyl and (hetero)aryl substituents

“…Compounds 8 , 15–17 , and 43 have also been synthesized and evaluated by Targacept, Inc. ( 8 : rα4β2*: K i = 18.7 nM; hα4β2*: K i = 20.2 nM; rα7*: 3277.9 nM; 15 : rα4β2*: K i = 12.2 nM; hα4β2*: K i = 10.4 nM; rα7*: 795.1 nM; 16 : rα4β2*: K i = 8.1 nM; hα4β2*: K i = 2.9 nM; rα7*: 230.3 nM; 17 : rα4β2*: K i = 101.6 nM; hα4β2*: K i = 44.4 nM; rα7*: 644.7 nM; 43 : rα4β2*: K i = 26.6 nM; hα4β2*: K i = 20.2 nM; rα7*: 211.2 nM). 22,23,28 Compound 18 has only been claimed in this patent but no biological data have been published. The use of a different radioligand and different tissues for the membrane preparation may account for some, but minor differences in K i values compared to our results.…”

“…Targacept, Inc. also synthesized and evaluated the 2-furanyl analog 30 as a nAChR ligand and the reported affinities (rα4β2*: K i = 31 nM using [ 3 H]nicotine on rat brain membrane fractions; hα4β2*: K i = 9.9 nM using [ 3 H]nicotine on SH-EP1 clonal cell membrane fractions; rα7*: 15 µM using [ 3 H]MLA on rat brain membrane fractions) correspond well with our data. 22,23,28 The N-methylpyrrol-2-yl derivative ( 59 ) showed less affinity for the α4β2* subtype compared to 30 and 31 , which could be due to its N-methyl substituent mimicking an ortho-substituent. In contrast to 44 (2-methylphenyl), which is lacking any affinity, 59 displayed a K i value of 661.6 nM for this subtype.…”

Comparative Study on the Use of Docking and Bayesian Categorization To Predict Ligand Binding to Nicotinic Acetylcholine Receptors (nAChRs) Subtypes

“…26,30 Numerous studies on virtual screening targeting nAChRs have also been reported by others in recent years. 31−41 Most of these studies have used molecular docking approach.…”