Bioorganic & Medicinal Chemistry Letters 2005-02-15

6'-Methylpyrido[3,4-b]norhomotropane: synthesis and outstanding potency in relation to the alpha4beta2 nicotinic receptor pharmacophore model.

David B Kanne, Motohiro Tomizawa, Kathleen A Durkin, John E Casida

Index: Bioorg. Med. Chem. Lett. 15 , 877-81, (2005)

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Abstract

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.