Synthesis and binding studies of epibatidine analogues as ligands for the nicotinic acetylcholine receptors.
Neuronal nicotinic acetylcholine receptors (nAChRs) are transmembrane ligand-gated ion channels. Recent research demonstrated that selective nAChR ligands may have therapeutic potential in a number of CNS diseases and disorders. The alkaloid epibatidine is a highly potent non-opioid analgesic and nAChR agonist, but too toxic to be a useful ligand. To develop ligands selective for distinct nAChR subtypes and with reduced toxicity, a series of epibatidine and homoepibatidine analogues were synthesized. (+/-)-8-Methyl-3-(pyridin-3-yl)-8-azabicyclo[3,2,1]oct-2-ene, showed high affinity towards alpha4beta2 (Ki=2 nM), subtype selectivity (alpha4beta2/alpha7 affinity ratio>100) and relatively low toxicity in mice and can be labeled with 11C and 18F as positron emission tomography (PET) tracers for imaging of nAChRs.
Mu
Linjing
L
Center for Radiopharmaceutical Sciences, Swiss Federal Institute of Technology Zurich, Paul Scherrer Institute, Villigen and University Hospital of Zürich, Rämistrasse 100, CH-8091 Zürich, Switzerland.
Drandarov
Konstantin
K
Bisson
William H
WH
Schibig
Anita
A
Wirz
Christa
C
Schubiger
P August
PA
Westera
Gerrit
G
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013329:Structure-Activity Relationship
D019086:Bridged Bicyclo Compounds, Heterocyclic; D008024:Ligands; D011725:Pyridines; D011978:Receptors, Nicotinic; C082748:epibatidine