AT-1001 Is a partial agonist with high affinity and selectivity at human and rat α3β4 nicotinic cholinergic receptors

Edward W. Tuan, Andrew G. Horti, Thao T. Olson, Yongiun Gao, Craig A. Stockmeier, Nour Al-Muhtasib, Carrie Bowman Dalley, Amanda E. Lewin, Barry B. Wolfe, Niaz Sahibzada, Yingxian Xiao, Kenneth J. Kellar

Research output: Contribution to journalArticle

Abstract

AT-1001 [N-(2-bromophenyl)-9-methyl-9-azabicyclo[3.3.1] nonan- 3-amine] is a high-affinity and highly selective ligand at α3β4 nicotinic cholinergic receptors (nAChRs) that was reported to decrease nicotine self-administration in rats. It was initially reported to be an antagonist at rat α3β4nAChRs heterologously expressed in HEK293 cells. Here we compared AT-1001 actions at rat and human α3β4 and α4β2 nAChRs similarly expressed in HEK 293 cells. We found that, as originally reported, AT-1001 is highly selective for α3β4receptors over α4β2 receptors, but its binding selectivity ismuch greater at human than at rat receptors, because of a higher affinity at human than at rat α3β4 nAChRs. Binding studies in human and rat brain and pineal gland confirmed the selectivity of AT-1001 for α3β4 nAChRs and its higher affinity for human compared with rat receptors. In patch-clamp electrophysiology studies, AT-1001 was a potent partial agonist with 65-70% efficacy at both human and rat α3β4 nAChRs. It was also a less potent and weaker (18%) partial agonist at α4β2 nAChRs. Both α3β4 and α4β2 nAChRs are upregulated by exposure of cells to AT-1001 for 3 days. Similarly, AT-1001 desensitized both receptor subtypes in a concentration-dependent manner, but it was 10 and 30 times more potent to desensitize human α3β4 receptors than rat α3β4 and human α4β2 receptors, respectively. After exposure to AT-1001, the time to recovery from desensitization was longest for the human α3β4 nAChR and shortest for the human α 4β2 receptor, suggesting that recovery fromdesensitization is primarily related to the dissociation of the ligand from the receptor.

Original languageEnglish (US)
Pages (from-to)640-649
Number of pages10
JournalMolecular Pharmacology
Volume88
Issue number4
DOIs
StatePublished - Oct 1 2015

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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  • Cite this

    Tuan, E. W., Horti, A. G., Olson, T. T., Gao, Y., Stockmeier, C. A., Al-Muhtasib, N., Dalley, C. B., Lewin, A. E., Wolfe, B. B., Sahibzada, N., Xiao, Y., & Kellar, K. J. (2015). AT-1001 Is a partial agonist with high affinity and selectivity at human and rat α3β4 nicotinic cholinergic receptors. Molecular Pharmacology, 88(4), 640-649. https://doi.org/10.1124/mol.115.099978