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

Abstract

3,7-Diazabicyclo[3.3.1]nonane (bispidine) based nicotinic acetylcholine receptor (nAChR) ligands have been synthesized and evaluated for nAChRs interaction. Diverse spacer motifs were incorporated between the hydrogen bond acceptor (HBA) part and a variety of substituted (hetero)aryl moieties. Bispidine carboxamides bearing spacer motifs often showed high affinity in the low nanomolar range and selectivity for the α4β2* nAChR. Compounds 15, 25, and 47 with Ki values of about 1 nM displayed the highest affinities for α4β2* nAChR. All evaluated compounds are partial agonists or antagonists at α4β2*, with reduced or no effects on α3β4* with the exception of compound 15 (agonist), and reduced or no effect at α7 and muscle subtypes.

The twin drug approach for novel nicotinic acetylcholine receptor ligands

“…The diazabicyclic system bispidine was prepared using our published method. 50,51 Subsequent removal of the N- t boc-protecting group by HCl in dioxane led to the desired products. The highest purity (95–99%) was obtained when purified on preparative HPLC using a gradient of MeOH/H 2 O.…”

“…51,52 [ 3 H]Epibatidine and [ 3 H]MLA were used as radioligands. Crude membrane fractions were prepared from Sprague-Dawley rat forebrains, pig adrenals or Torpedo californica electroplax to serve as receptor sources.…”

Ether and Carbamate Derivatives of 3-quinuclidinol and 3- hydroxymethylquinuclidine: Synthesis and Evaluation as Nicotinic Ligands

“…Nicotinic Acetylcholine Receptors (nAChRs) are pentameric membrane proteins belonging to the ligand-gated ion channel superfamily. A total of twelve (12) neuronal nAChR subunits are known that include nine (9) ( 2-10) and three (3) subunits ( 2-4) [1]. The nAChRs are composed of various combinations of these subunits that form homo or heteropentamers and are widely distributed throughout the central and peripheral nervous systems.…”

“…Evidence suggests that nAChR subtypes may serve as novel drug targets for treatment of CNS disorders including Alzheimer's Disease (AD), Parkinson's Disease (PD), L-dopa induced dyskinesia, addiction, attention deficit hyperactivity disorder (ADHD) and major depressive disorders [2,3]. Subtype selective nicotinic ligands have also been shown useful as pharmacological tools [4][5][6][7][8][9][10][11][12][13][14][15].…”

pH‐Gated Chloride Transport by a Triazine‐Based Tripodal Semicage

“…For the synthesis of 2 and 3,c ompound 5 was convertedi nto amine 7,f ollowing the reported procedure. [11] Free amine 7 was first reactedw ith pentafluorobenzylbromide to give the corresponding pentafluorobenzyl derivative (yield 95 %) which upon treatment with TFAf ollowed by neutralization gave free amine 8 (yield 96 %). In the final step, coupling of amine 8 with cyanuricc hloride in the presence of DIPEA furnished compound 2 (yield 35 %).…”