Novel Potent Ligands for the Central Nicotinic Acetylcholine Receptor:  Synthesis, Receptor Binding, and 3D-QSAR Analysis

Abstract

In the past few years the focus on central acetylcholine receptors has shifted from compounds with affinity for muscarinic acetylcholine receptors (mAChR) to compounds with affinity for nicotinic acetylcholine receptors (nAChR). The therapeutic potential includes treatment of a variety of diseases, e.g., Alzheimer's disease, Parkinson's disease, and Tourette's syndrome. This work describes the synthesis of six novel series of potent ligands with nanomolar affinity for the alpha4beta2 nAChR subtype. Structure-activity relationship (SAR) was evaluated by the calculation of a 3D-QSAR model. 3D-QSAR analysis of the compounds using the GRID/GOLPE methodology resulted in a model of high quality (R(2) = 0.97, Q(2) = 0.81). The coefficient plots reveal that the steric interactions between the target and our compounds are of major importance for the affinity. Bulky substituents in the 6-position of the pyridine ring will reduce the affinity of the compounds, whereas bulky ring systems including a sp(3)-nitrogen will increase the affinity of the compounds.

Structural and Functional Studies of the Modulator NS9283 Reveal Agonist-like Mechanism of Action at α4β2 Nicotinic Acetylcholine Receptors

“…Radioactive Ligand Binding-An Ls-AchBP/5-HT 3 AR chimera was stably expressed in HEK293 cells (CRL-1573, American Type Culture Collection) and prepared for binding experiments as described previously (21). Briefly, cell pellets were thawed, washed in 15 ml of Tris-HCl (50 mM, pH 7.4), treated with an Ultra-Turrax homogenizer, centrifuged for 10 min at 4°C and 25,000 relative centrifugal force, and resuspended in ice-cold Tris-HCl buffer (50 mM, pH 7.4 (22).…”

Intersubunit Bridge Formation Governs Agonist Efficacy at Nicotinic Acetylcholine α4β2 Receptors

“…3 H]cytisine as previously reported (38). Nonspecific binding was determined in the presence of 100 M (Ϫ)-nicotine.…”

The production of novolac oligomers

“…The number of arylsulphides showed potential clinical application, for example, for the treatment of Alzheimer's disease and Parkinson's disease, for the treatment of asthma and obstructive lung diseases, for the treatment of human immunodeficiency virus (HIV) [39][40][41][42][43][44].…”