Synthesis and pharmacological characterization of new neuronal nicotinic acetylcholine receptor ligands derived from Sazetidine-A.
The enantiomers of two analogs of Sazetidine-A as well as several other novel biosteric analogues were synthesized. Their binding affinities at three major nAChRs subtypes and selectivity profiles were determined. Though many (S)-enantiomers of Sazetidine-A analogs have high binding affinities and good subtype selectivities, it is not a general rule that (S)-enantiomers are better than their (R) counterparts. Compound 11, of which the ethynyl group was replaced by its' bioisostere-the triazole via click chemistry, showed a high binding affinity to α4β2 subtype (Ki=1.3 nM) and better selectivity to the α4β2 subtype over α3β4 subtype with that of Sazetidine-A. The azide compound 15, a potential photoaffinity label, showed improved high selectivity and similar binding property profile with that of Sazetidine-A. The biaryl analog 17 exhibited a much lower affinity as compared to Sazetidine-A indicating the importance of a 'long tail' side chain for α4β2 nAChR binding.
Center for Drug Discovery, Georgetown University Medical Center, Research Building EP07, 3970 Reservoir Road, NW, Washington, DC 20057, United States.
Yong
Y
Liu
Center for Drug Discovery, Georgetown University Medical Center, Research Building EP07, 3970 Reservoir Road, NW, Washington, DC 20057, United States.
Mikell
M
Paige
Department of Pharmacology and Physiology, Georgetown University School of Medicine, 3970 Reservoir Road, NW, Washington, DC 20057, United States.
Thao T
TT
Olson
Department of Pharmacology and Physiology, Georgetown University School of Medicine, 3970 Reservoir Road, NW, Washington, DC 20057, United States.
Nour
N
Al-Muhtasib
Department of Pharmacology and Physiology, Georgetown University School of Medicine, 3970 Reservoir Road, NW, Washington, DC 20057, United States.
Teresa
T
Xie
Center for Drug Discovery, Georgetown University Medical Center, Research Building EP07, 3970 Reservoir Road, NW, Washington, DC 20057, United States.
Shujie
S
Hou
Center for Drug Discovery, Georgetown University Medical Center, Research Building EP07, 3970 Reservoir Road, NW, Washington, DC 20057, United States.
Michael P
MP
White
Center for Drug Discovery, Georgetown University Medical Center, Research Building EP07, 3970 Reservoir Road, NW, Washington, DC 20057, United States.
Antoinette
A
Cordova
Center for Drug Discovery, Georgetown University Medical Center, Research Building EP07, 3970 Reservoir Road, NW, Washington, DC 20057, United States.
Jessica L
JL
Guo
Department of Pharmacology and Physiology, Georgetown University School of Medicine, 3970 Reservoir Road, NW, Washington, DC 20057, United States.
Kenneth J
KJ
Kellar
Department of Pharmacology and Physiology, Georgetown University School of Medicine, 3970 Reservoir Road, NW, Washington, DC 20057, United States. Electronic address: yxiao02@georgetown.edu.
Yingxian
Y
Xiao
Center for Drug Discovery, Georgetown University Medical Center, Research Building EP07, 3970 Reservoir Road, NW, Washington, DC 20057, United States. Electronic address: mb544@georgetown.edu.
Milton L
ML
Brown
D001384:Azetidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008024:Ligands; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013329:Structure-Activity Relationship
D001384:Azetidines; D008024:Ligands; D011725:Pyridines; D011978:Receptors, Nicotinic; C514816:sazetidine-A
Bioisostere; Biostere; Click chemistry; Nicotinic receptor; Photoaffinity label; Sazetidine A; nAChR α4β2