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.
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.
Linjing
L
Mu
Konstantin
K
Drandarov
William H
WH
Bisson
Anita
A
Schibig
Christa
C
Wirz
P August
PA
Schubiger
Gerrit
G
Westera
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