Chemistry and behavioral studies identify chiral cyclopropanes as selective alpha4beta2-nicotinic acetylcholine receptor partial agonists exhibiting an antidepressant profile.

Article Details

Citation

Copy to clipboard

Zhang H, Tuckmantel W, Eaton JB, Yuen PW, Yu LF, Bajjuri KM, Fedolak A, Wang D, Ghavami A, Caldarone B, Paterson NE, Lowe DA, Brunner D, Lukas RJ, Kozikowski AP

Chemistry and behavioral studies identify chiral cyclopropanes as selective alpha4beta2-nicotinic acetylcholine receptor partial agonists exhibiting an antidepressant profile.

J Med Chem. 2012 Jan 26;55(2):717-24. doi: 10.1021/jm201157c. Epub 2012 Jan 10.

PubMed ID

22171543 [ View in PubMed

]

Abstract

Despite their discovery in the early 20th century and intensive study over the last 20 years, nicotinic acetylcholine receptors (nAChRs) are still far from being well understood. Only a few chemical entities targeting nAChRs are currently undergoing clinical trials, and even fewer have reached the marketplace. In our efforts to discover novel and truly selective nAChR ligands, we designed and synthesized a series of chiral cyclopropane-containing alpha4beta2-specific ligands that display low nanomolar binding affinities and excellent subtype selectivity while acting as partial agonists at alpha4beta2-nAChRs. Their favorable antidepressant-like properties were demonstrated in the classical mouse forced swim test. Preliminary ADMET studies and broad screening toward other common neurotransmitter receptors were also carried out to further evaluate their safety profile and eliminate their potential off-target activity. These highly potent cyclopropane ligands possess superior subtype selectivity compared to other alpha4beta2-nAChR agonists reported to date, including the marketed drug varenicline, and therefore may fully satisfy the crucial prerequisite for avoiding adverse side effects. These novel chemical entities could potentially be advanced to the clinic as new drug candidates for treating depression.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Nicotine	Neuronal acetylcholine receptor subunit beta-2	IC 50 (nM)	430	N/A	N/A	Details
Nicotine	Neuronal acetylcholine receptor subunit beta-2	EC 50 (nM)	290	N/A	N/A	Details