Deconstruction of the alpha 4 beta 2 Nicotinic Acetylcholine Receptor Positive Allosteric Modulator Desformylflustrabromine

作者：German Nadezhda; Kim Jin Sung; Jain Atul; Dukat Malgorzata; Pandya Anshul; Ma Yilong; Weltzin Maegan; Schulte Marvin K; Glennon Richard A^*

来源：Journal of Medicinal Chemistry, 2011, 54(20): 7259-7267.

DOI：10.1021/jm200834x

Desformylflustrabromine (dFBr; 1), perhaps the first selective positive allosteric modulator of alpha 4 beta 2 neuronal nicotinic acetylcholine (nACh) receptors, was deconstructed to determine which structural features contribute to its actions on receptors expressed in Xenopus ooycytes using two-electrode voltage clamp techniques. Although the intact structure of 1 was found to be optimal, several deconstructed analogs retained activity. Neither the 6-bromo substituent nor the entire 2-position chain is required for activity. In particular, reduction of the olefinic side chain of 1, as seen with 6, not only resulted in retention of activity/potency but in enhanced selectivity for alpha 4 beta 2 versus alpha 7 nACh receptors. Pharmacophoric features for the allosteric modulation of alpha 4 beta 2 nACh receptors by 1 were identified.

• 出版日期2011-10-27