TY - JOUR
T1 - AT-1001 Is a partial agonist with high affinity and selectivity at human and rat α3β4 nicotinic cholinergic receptors
AU - Tuan, Edward W.
AU - Horti, Andrew G.
AU - Olson, Thao T.
AU - Gao, Yongiun
AU - Stockmeier, Craig A.
AU - Al-Muhtasib, Nour
AU - Dalley, Carrie Bowman
AU - Lewin, Amanda E.
AU - Wolfe, Barry B.
AU - Sahibzada, Niaz
AU - Xiao, Yingxian
AU - Kellar, Kenneth J.
N1 - Publisher Copyright:
Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2015/10/1
Y1 - 2015/10/1
N2 - 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.
AB - 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.
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U2 - 10.1124/mol.115.099978
DO - 10.1124/mol.115.099978
M3 - Article
C2 - 26162864
AN - SCOPUS:84946546387
SN - 0026-895X
VL - 88
SP - 640
EP - 649
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 4
ER -