title: Deconstruction of the α4β2 nicotinic acetylcholine receptor positive allosteric modulator desformylflustrabromine.
abstract: Desformylflustrabromine (dFBr; 1), perhaps the first selective positive allosteric modulator of α4β2 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 α4β2 versus α7 nACh receptors. Pharmacophoric features for the allosteric modulation of α4β2 nACh receptors by 1 were identified.
authors: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia 23298, United States.
authors: Nadezhda
authors: N
authors: German
authors: Jin-Sung
authors: JS
authors: Kim
authors: Atul
authors: A
authors: Jain
authors: Malgorzata
authors: M
authors: Dukat
authors: Anshul
authors: A
authors: Pandya
authors: Yilong
authors: Y
authors: Ma
authors: Maegan
authors: M
authors: Weltzin
authors: Marvin K
authors: MK
authors: Schulte
authors: Richard A
authors: RA
authors: Glennon
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D005260:Female; D006801:Humans; D006842:Hydrocarbons, Brominated / Q000737:chemistry / Q000494:pharmacology*; D026121:Indole Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011978:Receptors, Nicotinic / Q000502:physiology*; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
chemical_list: D006842:Hydrocarbons, Brominated; D026121:Indole Alkaloids; D011978:Receptors, Nicotinic; C524215:desformylflustrabromine; C403531:nicotinic receptor alpha4beta2