TY - JOUR T1 - Pharmacological Characterization of the Allosteric Modulator Desformylflustrabromine and Its Interaction with α4β2 Neuronal Nicotinic Acetylcholine Receptor Orthosteric Ligands JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 917 LP - 926 DO - 10.1124/jpet.110.167684 VL - 334 IS - 3 AU - Maegan M. Weltzin AU - Marvin K. Schulte Y1 - 2010/09/01 UR - http://jpet.aspetjournals.org/content/334/3/917.abstract N2 - Neuronal nicotinic acetylcholine receptors (nAChRs) are members of the Cys-loop superfamily of ligand-gated ion channels. nAChRs are involved in modulating nicotinic-based signal transmission in the central nervous system and are implicated in a range of disorders. Desformylflustrabromine (dFBr) is a positive allosteric modulator that potentiates α4β2 nAChRs. It has been reported that dFBr is selective for the α4β2 receptor relative to other common nAChR subtypes (Neurosci Lett 373:144–149, 2005). Coapplication of dFBr with acetylcholine (ACh) produces a bell-shaped dose–response curve with a peak potentiation of more than 265% (Bioorg Med Chem Lett 17:4855–4860, 2007) at dFBr concentrations <10 μM and inhibition of responses at concentrations >10 μM. The potentiation and inhibition components of dFBr-modulated responses were examined by using two-electrode voltage clamp and human α4β2 nAChRs expressed in Xenopus laevis oocytes. Currents to both partial and full agonists were potentiated by dFBr. Responses to low-efficacy agonists were potentiated significantly more than responses to high-efficacy agonists. Antagonist pIC50 values were unaffected by coapplication of dFBr. In addition to its potentiating effects, dFBr was able to induce current spikes when applied to desensitized receptors, suggestive of a shift in equilibrium from the desensitized to open conformation. In contrast to potentiation, inhibition of ACh responses by dFBr depends on membrane potential and is probably the result of open-channel block by dFBr and ACh. Our data indicate distinct mechanisms for the potentiation and inhibition components of dFBr action. dFBr could prove useful for therapeutic enhancement of responses at α4β2-containing synapses. ER -