des-Formylflustrabromine (dFBr): A Structure–Activity Study on Its Ability To Potentiate the Action of Acetylcholine at α4β2 Nicotinic Acetylcholine Receptors

The naturally occurring indole alkaloid des-formylflustrabromine (dFBr; 1) is one of the first agents shown to act as a selective positive allosteric modulator (PAM) at α4β2 nicotinic acetylcholine receptors (nAChRs). We previously deconstructed this agent to determine which of its structural features contribute to its actions and have identified an agent that might serve as the basis for a “working pharmacophore”. Here, we elaborate the dFBr (1; EC₅₀ = 0.2 μM) structure to identify how various structural modifications impact its actions. Electrophysiological studies with Xenopus laevis oocytes identified several compounds with dFBr-like potency and one, the 5-bromo analogue of 1 (i.e., 5-bromo dFBr; 25; EC₅₀ = 0.4 μM), with more than twice the efficacy of 1 as a PAM at α4β2 nAChRs.