Conformational analysis for some nonclassical antagonists of histamine H3 receptor

Abstract

AbstractA conformational search in vacuum for a series of 1,3‐substituted pyrrolidine derivatives has been performed using the AMBER, AM1, PM3, and MNDO methods. Conformational analysis of the pyrrolidine ligands suggests that these compounds could have many conformers that populate the low‐energy minima on the potential energy surface (PES). The conformational space occupied by the ligands is large and, in vacuum, the rotation barriers of different flexible bonds have energies between 0.5 and thousands of kcal/mol. By optimization, most conformers have energy barriers of 0–5 kcal/mol; thus, they could interconvert easily to obtain better interactions in the receptor active site. Optimized conformers having energy barriers of >5 kcal/mol display bad geometries with very large bond lengths and deformed rings. Shapes and heights of rotation barriers obtained through COSMO–AM1 single‐point calculations in water are similar to those obtained from single‐point calculations in vacuum. However, in water the energy barriers are lower, allowing most conformers to convert in other low‐energy conformers. The best conformers in vacuum and in water are different: the gas phase best conformer has a helical shape, while the best conformer in water has an extended shape. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007