Synthesis and structure-activity relationships of 3,8-diazabicyclo[4.2.0]octane ligands, potent nicotinic acetylcholine receptor agonists.
A series of potent neuronal nicotinic acetylcholine receptor (nAChR) ligands based on a 3,8-diazabicyclo[4.2.0]octane core have been synthesized and evaluated for affinity and agonist efficacy at the human high affinity nicotine recognition site (halpha4beta2) and in a rat model of persistent nociceptive pain (formalin model). Numerous analogs in this series exhibit picomolar affinity in radioligand binding assays and nanomolar agonist potency in functional assays, placing them among the most potent nAChR ligands known for the halpha4beta2 receptor. Several of the compounds reported in this study (i.e., 24, 25, 28, 30, 32, and 47) exhibit equivalent or greater affinity for the halpha4beta2 receptor relative to epibatidine, and like epibatidine, many exhibit robust analgesic efficacy in the rat formalin model of persistent pain.
Frost
Jennifer M
JM
Neuroscience Research, Abbott Laboratories, Abbott Park, IL 60064, USA. jennifer.frost@abbott.com
Bunnelle
William H
WH
Tietje
Karin R
KR
Anderson
David J
DJ
Rueter
Lynne E
LE
Curzon
Peter
P
Surowy
Carol S
CS
Ji
Jianquo
J
Daanen
Jerome F
JF
Kohlhaas
Kathy L
KL
Buckley
Michael J
MJ
Henry
Rodger F
RF
Dyhring
Tino
T
Ahring
Philip K
PK
Meyer
Michael D
MD
D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001667:Binding, Competitive; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008968:Molecular Conformation; D015394:Molecular Structure; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D009795:Octanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D010146:Pain / Q000188:drug therapy*; D011725:Pyridines / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000700:Analgesics; D019086:Bridged Bicyclo Compounds, Heterocyclic; D008024:Ligands; D018722:Nicotinic Agonists; D009795:Octanes; D011725:Pyridines; D011978:Receptors, Nicotinic; C403530:nicotinic receptor alpha3beta4; C403531:nicotinic receptor alpha4beta2; C082748:epibatidine; D002118:Calcium; C026728:octane