Chemistry and behavioral studies identify chiral cyclopropanes as selective α4β2-nicotinic acetylcholine receptor partial agonists exhibiting an antidepressant profile

Hankun Zhang, Werner Tückmantel, J. Brek Eaton, Po Wai Yuen, Li Fang Yu, Krishna Mohan Bajjuri, Allison Fedolak, Daguang Wang, Afshin Ghavami, Barbara Caldarone, Neil E. Paterson, David A. Lowe, Daniela Brunner, Ronald J. Lukas, Alan P. Kozikowski

Research output: Contribution to journalArticle

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 α4β2-specific ligands that display low nanomolar binding affinities and excellent subtype selectivity while acting as partial agonists at α4β2-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 α4β2-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.

Original languageEnglish (US)
Pages (from-to)717-724
Number of pages8
JournalJournal of Medicinal Chemistry
Volume55
Issue number2
DOIs
StatePublished - Jan 26 2012
Externally publishedYes

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Cyclopropanes
Nicotinic Receptors
Antidepressive Agents
Ligands
Neurotransmitter Receptor
Pharmaceutical Preparations
Clinical Trials
Safety
cyclopropane

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Chemistry and behavioral studies identify chiral cyclopropanes as selective α4β2-nicotinic acetylcholine receptor partial agonists exhibiting an antidepressant profile. / Zhang, Hankun; Tückmantel, Werner; Eaton, J. Brek; Yuen, Po Wai; Yu, Li Fang; Bajjuri, Krishna Mohan; Fedolak, Allison; Wang, Daguang; Ghavami, Afshin; Caldarone, Barbara; Paterson, Neil E.; Lowe, David A.; Brunner, Daniela; Lukas, Ronald J.; Kozikowski, Alan P.

In: Journal of Medicinal Chemistry, Vol. 55, No. 2, 26.01.2012, p. 717-724.

Research output: Contribution to journalArticle

Zhang, H, Tückmantel, 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 2012, 'Chemistry and behavioral studies identify chiral cyclopropanes as selective α4β2-nicotinic acetylcholine receptor partial agonists exhibiting an antidepressant profile', Journal of Medicinal Chemistry, vol. 55, no. 2, pp. 717-724. https://doi.org/10.1021/jm201157c
Zhang, Hankun ; Tückmantel, Werner ; Eaton, J. Brek ; Yuen, Po Wai ; Yu, Li Fang ; Bajjuri, Krishna Mohan ; Fedolak, Allison ; Wang, Daguang ; Ghavami, Afshin ; Caldarone, Barbara ; Paterson, Neil E. ; Lowe, David A. ; Brunner, Daniela ; Lukas, Ronald J. ; Kozikowski, Alan P. / Chemistry and behavioral studies identify chiral cyclopropanes as selective α4β2-nicotinic acetylcholine receptor partial agonists exhibiting an antidepressant profile. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 2. pp. 717-724.
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