6'-Methylpyrido[3,4-b]norhomotropane: synthesis and outstanding potency in relation to the alpha4beta2 nicotinic receptor pharmacophore model.
6'-Methylpyrido[3,4-b]norhomotropane [synthesis as the racemate reported here] is more potent at the alpha4beta2 nicotinic receptor than any previous bridged nicotinoid. The two nitrogens and 6'-methyl substituent are superimposable on the two nitrogens and 6-chloro substituent of epibatidine, with the best fit on comparing the chair conformer of the (1R)-pyridonorhomotropane with natural (1R)-epibatidine. In this pharmacophore model, the 6'-methyl substituent may be equivalent to the acetyl methyl of acetylcholine.
Kanne
David B
DB
Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, CA 94720-3112, USA.
Tomizawa
Motohiro
M
Durkin
Kathleen A
KA
Casida
John E
JE
D019086:Bridged Bicyclo Compounds, Heterocyclic; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009538:Nicotine / Q000031:analogs & derivatives; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology
C501166:6'-methylpyrido(3,4-b)norhomotropane; D019086:Bridged Bicyclo Compounds, Heterocyclic; D011725:Pyridines; D011978:Receptors, Nicotinic; D014326:Tropanes; C403531:nicotinic receptor alpha4beta2; C055134:pyrido(3,4-b)norhomotropane; D009538:Nicotine; C082748:epibatidine