Design and Synthesis of Nicotinic Acetylcholine Receptor Antagonists and their Effect on Cognitive Impairment

Abstract

Structure modification of a lead compound (NSC13378) was accomplished in the present work by an in silico target-based design aimed at ligands acting on the nicotinic acetylcholine receptor (nAChR) for neurodegenerative diseases. A 187-compound focused library derived from the scaffold of the lead compound was screened against acetylcholine-binding proteins (AChBPs). Six compounds were identified and synthesized for binding and biological evaluations. Five compounds were found to bind with AChBPs. Among these compounds, QN1 and BZ1 showed the highest affinity binding with AChBP, with Kd values of 260 and 10 nm, respectively. Functional assays on isolated cell lines containing ligand-gated ion channels revealed that QN1 and BZ1 are a4b2-nAChR antagonists. QN1 and BZ1 significantly alleviated the memory impairment caused by the muscarinic cholinergic antagonist scopolamine (p < 0.05) in mice. Our findings demonstrate the potential of nAChR antagonists in drug development for cognitive impairments.

Substituted 2-Aminopyrimidines Selective for α7-Nicotinic Acetylcholine Receptor Activation and Association with Acetylcholine Binding Proteins

“…Several new and redesigned nAChR agonists with the capacity to cross the blood–brain barrier have shown cognitive improvements in animal testing. − These compounds are typically amines, such as nicotine and epibatidine, or imines, such as anabaseines. They contain a moderately strong base and interact as a protonated form to associate with a backbone carbonyl oxygen on the principal subunit interface and also possess a dipole or weaker base that interacts with positions on the complementary subunit at the subunit interface.…”

In Silico Finding of Key Interaction Mediated α3β4 and α7 Nicotinic Acetylcholine Receptor Ligand Selectivity of Quinuclidine-Triazole Chemotype

“…The molecular docking of non-flexible amino acid residues was performed by AutoDock4.2 [ 35 ], with genetic algorithm (GA) parameters as described by our previous study [ 45 ]. The parameters included: 100 GA runs, a population size of 150, a maximum of 10,000,000 evaluations, and a maximum of 27,000 generations.…”

Dual Nicotinic Acetylcholine Receptor α4β2 Antagonists/α7 Agonists: Synthesis, Docking Studies, and Pharmacological Evaluation of Tetrahydroisoquinolines and Tetrahydroisoquinolinium Salts

“…[5][6][7][8][9] In comparison, antagonists are far less studied, despite their substantial therapeutic potential. [10][11][12][13][14][15][16][17][18][19][20] Most of the available nAChR antagonists are natural products such as methyllycaconitine (MLA), αbungarotoxin, ibogaine, d-tubocurarine, α-conotoxins and dihydro-β-erythroidine (DHβE), the latter being a widely used selective antagonist of β2-containing heteromeric nAChRs and a semisynthetic member of the Erythrina alkaloid family. 21,22 We recently reported the design, synthesis and pharmacological evaluation of 21 analogs of aromatic Erythrina alkaloids as nAChR antagonists and found that the structurally simple tetrahydroisoquinoline 1 (also known as O-methylcorypalline) 23,24 displayed submicromolar binding affinity at the α4β2 nAChR and more than 300-fold binding selectivity over the α4β4, α3β4 and α7 subtypes (see Figure 1A).…”

“…The nicotinic acetylcholine receptors (nAChRs), a heterogeneous family of ligand-gated ion channels widely distributed throughout the peripheral and central nervous systems, are involved in a broad range of psychiatric and neurodegenerative disorders such as schizophrenia, attention deficit hyperactivity disorder, depression, Alzheimer’s and Parkinson’s diseases, pain, and substance abuse. − Considerable efforts have been put into the design of agonists (based on scaffolds such as nicotine, varenicline, cytisine, and epibatidine) as well as positive allosteric modulators targeting the neuronal nAChRs. − In comparison, antagonists are far less studied despite their substantial therapeutic potential. − Most of the available nAChR antagonists are natural products such as methyllycaconitine (MLA), α-bungarotoxin, ibogaine, d -tubocurarine, α-conotoxins, and dihydro-β-erythroidine (DHβE), the latter being a widely used selective antagonist of β2-containing heteromeric nAChRs and a semisynthetic member of the Erythrina alkaloid family. , We recently reported the design, synthesis, and pharmacological evaluation of 21 analogues of aromatic Erythrina alkaloids as nAChR antagonists and found that the structurally simple tetrahydroisoquinoline 1 (also known as O -methylcorypalline) , displayed submicromolar binding affinity at the α4β2 nAChR and more than 300-fold binding selectivity over the α4β4, α3β4, and α7 subtypes (see Figure A) …”