NMR Study of Conformational Preferences of Inhibitors of Monoamine Uptake

Abstract

We have used the recently developed tensor decomposition 3D-QSAR method to predict the conformation and alignment of cocaine derivatives bound to the monoamine transporters, NET, DAT and SERT. The analysis revealed that the ligands bind to the receptors in a conformation with the 3b-aryl group orthogonal or approximately orthogonal to the tropane ring. Semi rigid ligands have been prepared with a 3b-aryl group having strong conformational preferences for this orientation. Two compounds had affinities for the DAT and SERT in the low nanomolar range. The solution conformation of one compound has been determined and the results support the results of the 3D-QSAR analysis. Comparisons of affinities and selectivities of these ligands are discussed.We have recently published a methodology for exploring the effects of conformation and alignment on biological activity using descriptor data developed from molecular field analysis of the structures. The structure-activity data are analyzed by 3-way PLS [1]. The application of this method to published binding data of ligands to the monoamine transporters suggests that selectivity and/or affinity may be determined in large part by ligand conformation.We have designed, synthesized and evaluated a number of rigid and semi-rigid tropane derivatives and evaluated their binding to the transporter proteins [2] and the data for two analogs, ( / À )1a and ( / À )1b shown in Figure 1, are reported here.The compounds, 2a and 2b, are a-and b-disubstituted naphthylethylenes which are known to have strong conformational preferences [4,5]. For example, 2a with R 1 CH 3 , has been shown with temperature-dependent nmr to have a barrier to rotation through a transition state in which the naphthyl group is planar to the ethylene group of ) 26 kcal/mole. Similarly, 2b with R 1 CH 3 , has a barrier to rotation through a planar transition state of about 6.5 kcal/ mole. By building this system into the tropane ring, as in 1a and 1b, it is possible to have ligands with fewer degrees of internal rotational degrees of freedom. In addition, this would overcome unfavorable entropic effects on binding [6].To explore the conformational properties of 1a and 1b, their structures were built using the Cerius2 program [7] and the Universal Open Force Field [8]. The molecules were modeled in the neutral form and partial charges were applied using the Charge-Equilibration [9] method. Structures were minimized to convergence. The global minima and higher energy wells were found by performing a systematic energy search where each torsion angle was rotated in 308 increments. This analysis of 1a shows that its lowest energy conformation has the naphthyl group with a 38 Quant. Struct.-Act. Relat., 21 (

Consensus Molecular Alignment Based on Generalized Procrustes Analysis

“…The compounds in the data set are all potent inhibitors of dopamine uptake by the dopamine transporter protein . They are somewhat flexible, and there is evidence that there are conformational preferences in binding of cocaine and its derivatives to the protein . In this study, it was realized that a generalized consensus alignment rule should be used to study the effect of conformation/alignment on binding to the transporter protein.…”