TY  - JOUR
PY  - 2011//
TI  - Discovery of isoxazole analogues of sazetidine-A as selective α4β2-nicotinic acetylcholine receptor partial agonists for the treatment of depression
JO  - Journal of medicinal chemistry
A1  - Liu, Jianhua
A1  - Yu, Li-Fang
A1  - Eaton, J. Brek
A1  - Caldarone, Barbara
A1  - Cavino, Katie
A1  - Ruiz, Christina
A1  - Terry, Matthew
A1  - Fedolak, Allison
A1  - Wang, Daguang
A1  - Ghavami, Afshin
A1  - Lowe, David A.
A1  - Brunner, Dani
A1  - Lukas, Ronald J.
A1  - Kozikowski, Alan P.
SP  - 7280
EP  - 7288
VL  - 54
IS  - 20
N2  - 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.<p /> <p>Language: en</p>
LA  - en
SN  - 0022-2623
UR  - http://dx.doi.org/10.1021/jm200855b
ID  - ref1
ER  -