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

Abstract

3,7-Diazabicyclo[3.3.1]nonane is a naturally occurring scaffold interacting with nicotinic acetylcholine receptors (nAChRs). When one nitrogen of the 3,7-diazabicyclo[3.3.1]nonane scaffold was implemented in a carboxamide motif displaying a hydrogen bond acceptor (HBA) functionality, compounds with higher affinities and subtype selectivity for α4β2(∗) were obtained. The nature of the HBA system (carboxamide, sulfonamide, urea) had a strong impact on nAChR interaction. High affinity ligands for α4β2(∗) possessed small alkyl chains, small un-substituted hetero-aryl groups or para-substituted phenyl ring systems along with a carboxamide group. Electrophysiological responses of selected 3,7-diazabicyclo[3.3.1]nonane derivatives to Xenopus oocytes expressing various nAChR subtypes showed diverse activation profiles. Compounds with strongest agonistic profiles were obtained with small alkyl groups whereas a shift to partial agonism/antagonism was observed for aryl substituents.

Keywords: 1,2-dimethoxyethane; 3,7-Diazabicyclo[3.3.1]nonane; 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid; 4-(dimethylamino)pyridine; BBB; Bispidine; CD(3)OD; CDCl(3); CH(2)Cl(2); CNS; D(2)O; DCC; DMAP; DME; DMF; Et(2)O; Et(3)N; EtOAc; HBA; HCl; HEPES; HEPES-buffered salt solution; HSS; K(2)CO(3); KBr; KMnO(4); KOH; MeCN; MeI; MeOH; MgSO(4); N,N-dimethylformamide; N,N′-dicyclohexylcarbodiimide; NaHCO(3); NaOH; Nicotinic acetylcholine receptor; PE; PEI; Pd/C; Ro5; Structure–activity relationship; THF; TPSA; TRIS; ZnBr(2); acetonitrile; blood–brain barrier; central nervous system; deuterium oxide; deuterochloroform; dichloromethane; diethyl ether; ethyl acetate; hydrogen bond acceptor; hydrogen chloride; iodomethane; magnesium sulfate; methanol; nAChR; nicotinic acetylcholine receptor; palladium on activated charcoal; petroleum ether; poly(ethyleneimine); potassium bromide; potassium carbonate; potassium hydroxide; potassium permanganate; rule of five; sodium hydrogen carbonate; sodium hydroxide; tetradeuteromethanol; tetrahydrofuran; topological polar surface area; tri(hydroxymethyl)aminomethane; triethylamine; zinc bromide.

Figure 1

Structures of acetylcholine 1, the natural products nicotine 2, and cytisine 3, 3-(pyridine-3-yl)-cytisine (3PC) 4 and the FDA approved drug varenicline 5.

Figure 2

3,7-diazabicyclo[3.3.1]nonane based compounds

Figure 3

Responses of oocytes expressing diverse nAChR subtypes to 1 or 10 µM of selected compounds (numbering are following the sequence in the tables) relative to ACh control responses. Responses of oocytes expressing diverse nAChRs to compounds co-applied at 1 µM with ACh compared to responses to ACh alone. Bars above zero indicate additive effects; bars below zero indicate reduced responses.

Scheme 1

Synthesis of compounds. Reagents and conditions: (a) (CH₂O)_n, BnNH₂, AcOH, MeOH, [Ar] reflux, 6 h; (b) N₂H₄ (80%), NaOH, diethylene glycol, 125 °C, 2 h, then Dean Stark trap, 140 °C, 8 h; (c) HCl/1,4-dioxane (4M), rt, 12 h; (d) Pd/C (5%), H₂ (2–4 bar), MeOH, rt, 4–24 h; (e) carboxyl chloride, Et₃N, toluene, rt, 2 h; (f) sulfonyl chloride, Et₃N, toluene, rt, 2 h; (g) carbamoyl chloride, Et₃N, toluene, rt, 2 h; (h) CDI, THF, reflux, 2 h = 14; then MeI, MeCN, THF, rt, 24 h, then R-COOH, Et₃N, MeCN, rt, 12–120 h; (i) R-COOH, DCC, DMAP, CH₂Cl₂, 0 °C to rt, 12 h; for Boc-56: 4-hydroxybenzoic acid, DCC, THF, rt, 24 h; (j) 64, 65 or 66, MeI, MeCN, rt, 24h; then 13, CH₂Cl₂, Et₃N, rt, 24h.; (k) HCl/1,4-dioxane (4M), rt, 4 h; (l) anhydr. ZnBr₂, CH₂Cl₂, rt, 12–120 h; (m) CDI, THF, reflux, 16 h; (n) alkyl iodide, K₂CO₃, DMF, rt, 12 h