Discovery of isoxazole analogues of sazetidine-A as selective α4β2-nicotinic acetylcholine receptor partial agonists for the treatment of depression

Jianhua Liu; Li-Fang Yu; J Brek Eaton; Barbara Caldarone; Katie Cavino; Christina Ruiz; Matthew Terry; Allison Fedolak; Daguang Wang; Afshin Ghavami; David A Lowe; Dani Brunner; Ronald J Lukas; Alan P Kozikowski

doi:10.1021/jm200855b

Discovery of isoxazole analogues of sazetidine-A as selective α4β2-nicotinic acetylcholine receptor partial agonists for the treatment of depression

J Med Chem. 2011 Oct 27;54(20):7280-8. doi: 10.1021/jm200855b. Epub 2011 Sep 30.

Authors

Jianhua Liu¹, Li-Fang Yu, J Brek Eaton, Barbara Caldarone, Katie Cavino, Christina Ruiz, Matthew Terry, Allison Fedolak, Daguang Wang, Afshin Ghavami, David A Lowe, Dani Brunner, Ronald J Lukas, Alan P Kozikowski

Affiliation

¹ Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antidepressive Agents / chemical synthesis*
Antidepressive Agents / pharmacokinetics
Antidepressive Agents / pharmacology
Azetidines / chemical synthesis*
Azetidines / pharmacokinetics
Azetidines / pharmacology
Behavior, Animal / drug effects
Binding, Competitive
Blood Proteins / metabolism
Drug Partial Agonism
Humans
In Vitro Techniques
Isoxazoles / chemical synthesis*
Isoxazoles / pharmacokinetics
Isoxazoles / pharmacology
Mice
Microsomes, Liver / metabolism
Nicotinic Agonists / chemical synthesis*
Nicotinic Agonists / pharmacokinetics
Nicotinic Agonists / pharmacology
Protein Binding
Pyridines / chemical synthesis*
Pyridines / pharmacokinetics
Pyridines / pharmacology
Rats
Receptors, Neurotransmitter / metabolism
Receptors, Nicotinic / physiology*
Structure-Activity Relationship

Substances

Antidepressive Agents
Azetidines
Blood Proteins
Isoxazoles
Nicotinic Agonists
Pyridines
Receptors, Neurotransmitter
Receptors, Nicotinic
alpha(4)beta(4) nicotinic receptor
sazetidine-A

Abstract

Publication types

MeSH terms

Substances

Grants and funding