posted on 2003-04-22, 00:00authored byHolger Gohlke, Simone Schwarz, Daniela Gündisch, Maria Cristina Tilotta, Alexander Weber, Thomas Wegge, Gunther Seitz
Three-dimensional quantitative structure−activity relationship methods, the comparative
molecular field analysis (CoMFA) and the comparative molecular similarity indices analysis
(CoMSIA), were applied using a training set of 45 ligands of the (α4)2(β2)3 nicotinic acetylcholine
receptor (nAChR). All compounds are related to (−)-epibatidine, (−)-cytisine, (+)-anatoxin-a,
and (−)-ferruginine, and additionally, novel diazabicyclo[4.2.1]nonane- and quinuclidin-2-ene-based structures were included. Their biological data have been determined by utilizing the
same experimental protocol. Statistically reliable models of good predictive power (CoMFA
r2 = 0.928, q2 = 0.692, no. of components = 3; CoMSIA r2 = 0.899, q2 = 0.701, no. of components = 3) were achieved. The results obtained were graphically interpreted in terms of field
contribution maps. Hence, physicochemical determinants of binding, such as steric and
electrostatic and, for the first time, hydrophobic, hydrogen bond donor, and hydrogen bond
acceptor properties, were mapped back onto the molecular structures of a set of nAChR
modulators. In particular, changes in the binding affinity of the modulators as a result of
modifications in the aromatic ring systems could be rationalized by the steric, electrostatic,
hydrophobic, and hydrogen bond acceptor properties. These results were used to guide the
rational design of new nAChR ligands such as 48−52 and 54, which were subsequently
synthesized for the first time and tested. Key steps of our synthetic approaches were successfully
applied Stille and Suzuki cross-coupling reactions. Predictive r2 values of 0.614 and 0.660 for
CoMFA and CoMSIA, respectively, obtained for 22 in part previously unknown ligands for the
(α4)2(β2)3 subtype, demonstrate the high quality of the 3D QSAR models.