title: Discovery of isoxazole analogues of sazetidine-A as selective α4β2-nicotinic acetylcholine receptor partial agonists for the treatment of depression.
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.
authors: Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States.
authors: Jianhua
authors: J
authors: Liu
authors: Li-Fang
authors: LF
authors: Yu
authors: J Brek
authors: JB
authors: Eaton
authors: Barbara
authors: B
authors: Caldarone
authors: Katie
authors: K
authors: Cavino
authors: Christina
authors: C
authors: Ruiz
authors: Matthew
authors: M
authors: Terry
authors: Allison
authors: A
authors: Fedolak
authors: Daguang
authors: D
authors: Wang
authors: Afshin
authors: A
authors: Ghavami
authors: David A
authors: DA
authors: Lowe
authors: Dani
authors: D
authors: Brunner
authors: Ronald J
authors: RJ
authors: Lukas
authors: Alan P
authors: AP
authors: Kozikowski
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001384:Azetidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive; D001798:Blood Proteins / Q000378:metabolism; D054333:Drug Partial Agonism; D006801:Humans; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000502:physiology*; D013329:Structure-Activity Relationship
chemical_list: D000928:Antidepressive Agents; D001384:Azetidines; D001798:Blood Proteins; D007555:Isoxazoles; D018722:Nicotinic Agonists; D011725:Pyridines; D017981:Receptors, Neurotransmitter; D011978:Receptors, Nicotinic; C427403:alpha(4)beta(4) nicotinic receptor; C514816:sazetidine-A