Deconstruction of the α4β2 Nicotinic Acetylcholine Receptor Positive Allosteric Modulator Desformylflustrabromine

Abstract

des -Formylflustrabromine (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 2-electrode voltage clamp techniques. Although the intact structure of 1 was found 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.

Desformylflustrabromine (dFBr) and [3H]dFBr-Labeled Binding Sites in a Nicotinic Acetylcholine Receptor

“…dFBr hydrochloride and des-methyl dFBr hydrochloride (6-bromo-2-(1,1-dimethylallyl)tryptamine) were synthesized as previously described (German et al, 2011 …”

“…1), isolated originally from the marine bryozoan Flustra foliacea (Peters et al, 2002), acts as a neuronal nAChR PAM, enhancing, at concentrations ,1 mM, peak ACh responses of a4b2 (Sala et al, 2005;Kim et al, 2007;German et al, 2011) and a2b2 (Pandya and Yakel, 2011) nAChRs expressed in Xenopus oocytes. At higher concentrations, dFBr inhibited these receptors and a7 nAChRs (Kim et al, 2007).…”

Activation of the α7 nicotinic ACh receptor induces anxiogenic effects in rats which is blocked by a 5-HT1a receptor antagonist

“…Nicotinic acetylcholine receptors (nAChRs) are cationic-conducting ion channels belonging to the cys-loop ligand-gated ion channel superfamily (Brams et al, 2011; Gay and Yakel, 2007; German et al, 2011; Pandya and Yakel, 2011b; Yakel and Shao, 2004). The neuronal nAChRs are either homomeric or heteromeric pentamers with combinations of α (α2 – α10) and β (β2 – β4) subunits, which have different pharmacological and biophysical properties (Arias, 2006; Gotti et al, 2007).…”

Recent progress in neuroactive marine natural products

“…N -demethylation reduced potency by 50%, and the bromine atoms influenced potency but not functional activity. 153 …”