Synthesis of 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane, 2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane, and 2-(pyridin-3-yl)-1-azabicyclo[3.2.1]octane, a class of potent nicotinic acetylcholine receptor-ligands.
In an attempt to generate nicotinic acetylcholine receptor (nAChR) ligands selective for the alpha4beta2 and alpha7 subtype receptors we designed and synthesized constrained versions of anabasine, a naturally occurring nAChR ligand. 2-(Pyridin-3-yl)-1-azabicyclo[2.2.2]octane, 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane, and several of their derivatives have been synthesized in both an enantioselective and a racemic manner utilizing the same basic synthetic approach. For the racemic synthesis, alkylation of N-(diphenylmethylene)-1-(pyridin-3-yl)methanamine with the appropriate bromoalkyltetrahydropyran gave intermediates which were readily elaborated into 2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane and 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane via a ring opening/aminocyclization sequence. An alternate synthesis of 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane via the alkylation of N-(1-(pyridin-3-ylethylidene)propan-2-amine has also been achieved. The enantioselective syntheses followed the same general scheme, but utilized imines derived from (+)- and (-)-2-hydroxy-3-pinanone. Chiral HPLC shows that the desired compounds were synthesized in >99.5% ee. X-ray crystallography was subsequently used to unambiguously characterize these stereochemically pure nAChR ligands. All compounds synthesized exhibited high affinity for the alpha4beta2 nAChR subtype ( K i < or = 0.5-15 nM), a subset bound with high affinity for the alpha7 receptor subtype ( K i < or = 110 nM), selectivity over the alpha3beta4 (ganglion) receptor subtype was seen within the 2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane series and for the muscle (alpha1betagammadelta) subtype in the 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane series.
Bhatti
Balwinder S
BS
Targacept, Inc., 200 East 1st Street, Suite 300, Winston-Salem, North Carolina 27101-4165, USA. bhattib@targacept.com
Strachan
Jon-Paul
JP
Breining
Scott R
SR
Miller
Craig H
CH
Tahiri
Persida
P
Crooks
Peter A
PA
Deo
Niranjan
N
Day
Cynthia S
CS
Caldwell
William S
WS
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011812:Quinuclidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism
C111220:2-(3-pyridinyl)-1-azabicyclo(2.2.2)octane; C484276:2-(3-pyridyl)-1-azabicyclo(3.2.2)nonane; C529505:2-(pyridin-3-yl)-1-azabicyclo(2.2.2)octane; D001643:Bridged Bicyclo Compounds; D008024:Ligands; D011725:Pyridines; D011812:Quinuclidines; D011978:Receptors, Nicotinic