Structure – activity relationships and determinants of selectivity for congeners of the selective α7 partial agonist 3‐(2,4‐dimethoxybenzylidene)‐anabaseine (DMXBA or GTS‐21) with the ACh binding proteins (AChBPs)

• Published in: The FASEB journal 2006-03, Vol.20 (4), p.A244-A244
• Main Authors: Talley, Todd T, Kem, William R., Soti, Ferenc S., Tsigelny, Igor, Hibbs, Ryan E., Taylor, Palmer
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.20.4.A244-b

Nicotinic ACh receptors (nAChRs) are prototypic members of the ligand‐gated ion channel family of receptors. AChBPs identified in the fresh and saltwater snails, Lymnaea stagnalis (L), Bulinus truncatus (B) and Aplysia californica (A), have been used as soluble surrogates for the extracellular domain of nAChRs. By combining equilibrium binding measurements, absorption and fluorescence spectroscopy, molecular modeling and X‐ray crystallography, we have elucidated further the molecular determinants of structure, function and selectivity. DMXBA selectively stimulates α7 nAChRs and enhances cognition and sensory gating. The O‐demethylated primary metabolites of DMXBA retain the same activity profile on α7 receptors, but are more efficacious in stimulating the human α7 nAChR (Kem et al., 2004). In our current study we examine a series of 24 structurally related benzylidene‐anabaseines (BAs), including DMXBA, and contrast the results with those obtained for epibatidine and nicotine. Using [3H]‐epibatidine as the competitor the rank order of Kd values were determined (400 pM ‐ 250 nM, 30 nM ‐ 5 μM and 2 nM ‐ 1 mM for L, B and A). Further, the unusual conjugation of BAs enables one to examine electronic configuration and ionization equilibria in the bound state. Our findings on ligand binding are correlated with those obtained by molecular modeling, spectroscopic and docking experiments. NIH R37‐GM18360, F32 NS043063 and RO1‐MH6142