820231-95-6

Usage

Biological Activity

Subtype-selective α 4 β 2 nicotinic acetylcholine receptor ligand (K i values are 0.26 and 54 nM at α 4 β 2 and α 3 β 4 receptors respectively). May act as a silent desensitizer or as an agonist (EC 50 = 1.1 nM for nAChR-stimulated dopamine release). Exhibits analgesic activity in vivo .

Upstream product

• 928-90-5 5-hexyl-1-ol 
• 186593-31-7 (S)-2-(5-bromo-pyridin-3-yloxymethyl)-azetidine-1-carboxylic acid tert-butyl ester 

Relevant academic research and scientific papers

Sazetidine-A, a novel ligand that desensitizes α4β2 nicotinic acetylcholine receptors without activating them

Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels found throughout the central and peripheral nervous systems. They are crucial to normal physiology and have been clearly implicated in nicotine addiction. In addition, they are possible therapeutic targets in a wide range of pathological conditions, including cognitive disorders, Parkinson's disease, and neuropathic pain. Nicotinic ligands are usually classified as agonists (or partial agonists), competitive antagonists, or noncompetitive antagonists. Sazetidine-A is a new nicotinic ligand that shows a different pharmacological profile from any of these known classes of ligands. Sazetidine-A competes with very high binding affinity (Ki ≈ 0.5 nM) and selectivity for the α4β2 nAChR subtype (Ki ratio α3β4/ α4β2 ～ 24,000). Despite its high affinity, sazetidine-A neither activates nAChR channel function nor prevents channel activation when it is applied simultaneously with nicotine. However, when it is pre-incubated for 10 min with the receptors, it potently blocks nicotine-stimulated α4β2 nAChR function (IC50 ≈ 30 nM). The action of sazetidine-A may be explained by its very low affinity for the resting conformation of the α4β2 nAChRs, and its very high affinity for the desensitized state of the receptor. We propose that sazetidine-A is a "silent desensitizer" of nAChRs, meaning that it desensitizes the receptor without first activating it. Furthermore, comparison of the effects of sazetidine-A and nicotine at α4β2 nAChRs suggests that the predominant effects of nicotine and other nicotinic agonists are related to desensitization of the receptors and that sazetidine-A potently mimics these effects. Copyright

SILENT DESENSITIZERS OF NEURONAL NACHR AND METHODS OF USE THEREOF

One aspect of the present invention relates to heterocyclic compounds that are ligands for nicotinic acetylcholine receptors. A second aspect of the invention relates to the use of a compound of the invention for modulation of a mammalian nicotinic acetylcholine receptor.

NICOTINIC DESENSITIZERS AND METHODS OF SELECTING, TESTING, AND USING THEM

The present invention discloses nicotinic desensitizers and methods of selecting, testing, and using them. The present invention provides methods for selecting nicotinic desensitizers from one or more compounds by using receptor, cell, and tissue models; and methods for testing one or more nicotinic desensitizers for their therapeutic utility by using animal models. The present invention also provides compounds of formula (I) and (II) as nicotinic desensitizers. Nicotinic desensitizers of the present invention are useful for the treatment of a wide range of conditions, diseases, and disorders.