Synthesis and nicotinic acetylcholine receptor binding properties of bridged and fused ring analogues of epibatidine.
Epibatidine analogues 3- 5, possessing the pyridine ring fused to the 2,3 position of the 7-azabicyclo[2.2.1]heptane ring, and analogue 8a, possessing a benzene ring fused to the 5,6 position, were synthesized by procedures involving key steps of trapping 2,3-pyridyne, 3,4-pyridyne, and benzyne with tert-butyl 1 H-pyrrole-1-carboxylate. Two epibatidine analogues, 6 and 7, which have the 2'-chloropyridine ring bridged to the 7-azabicyclo[2.2.1]heptane ring via a methylene group, were synthesized, where the key step was an intramolecular reductive palladium-catalyzed Heck-type coupling. Even though the conformationally restricted epibatidine analogues, 3- 7, and the benzo analogue 8a possess nAChR pharmacophore features thought to be needed for alpha(4)beta(2) binding, they all showed low affinity for nAChRs relative to epibatidine. These studies provide new information concerning the pharmacophore for nAChRs and suggest that nitrogen lone-pair directionality and steric factors may be important. Interestingly, N-methylepibatidine, prepared as a standard compound for the study of bridged analogues 6 and 7, was a potent nAChR mixed agonist antagonist.
Carroll
F Ivy
FI
Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709, USA. fic@rti.org
Robinson
T Philip
TP
Brieaddy
Lawrence E
LE
Atkinson
Robert N
RN
Mascarella
S Wayne
SW
Damaj
M Imad
MI
Martin
Billy R
BR
Navarro
Hernán A
HA
D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000700:Analgesics; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C082748:epibatidine