Citation

Liu J, Yu LF, Eaton JB, Caldarone B, Cavino K, Ruiz C, Terry M, Fedolak A, Wang D, Ghavami A, Lowe DA, Brunner D, Lukas RJ, Kozikowski AP. J. Med. Chem. 2011; 54(20): 7280-7288.

Copyright

(Copyright © 2011, American Chemical Society)

DOI

10.1021/jm200855b

PMID

21905669

PMCID

PMC3197876

Abstract

Depression, a common neurological condition, is one of the leading causes of disability and suicide worldwide. Standard treatment, targeting monoamine transporters selective for the neurotransmitters serotonin and noradrenaline, is not able to help many patients that are poor responders. This study advances the development of sazetidine-A analogues that interact with α4β2 nicotinic acetylcholine receptors (nAChRs) as partial agonists and that possess favorable antidepressant profiles. The resulting compounds that are highly selective for the α4β2 subtype of nAChR over α3β4-nAChRs are partial agonists at the α4β2 subtype and have excellent antidepressant behavioral profiles as measured by the mouse forced swim test. Preliminary absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies for one promising ligand revealed an excellent plasma protein binding (PPB) profile, low CYP450-related metabolism, and low cardiovascular toxicity, suggesting it is a promising lead as well as a drug candidate to be advanced through the drug discovery pipeline.

Language: en

Keywords

Humans; Animals; In Vitro Techniques; Rats; Antidepressive Agents; Mice; Structure-Activity Relationship; Pyridines; Isoxazoles; Nicotinic Agonists; Microsomes, Liver; Behavior, Animal; Binding, Competitive; Azetidines; Receptors, Neurotransmitter; Protein Binding; Blood Proteins; Receptors, Nicotinic; Drug Partial Agonism