n integrated QSAR/molecular modeling study is carried out on a series of baclofen analogues with the aim of addressing the role of their aromatic moiety in GABAB receptor binding and activation. The strong correlation found between electronic descriptors (HOMO and LUMO orbital energies) and the biological activity expressed as receptor binding is discussed also on the basis of available experimental mutagenesis data and of the results obtained from homology modeling of GABAB receptor. In particular, it can be inferred from the QSAR analysis that the ability of being involved in aromatic−aromatic π interaction is the distinctive feature of the p-chlorophenyl moiety of baclofen. This conclusion is confirmed by homology modeling and docking studies which indicate that the p-chlorophenyl moiety of baclofen is disposed into a pocket formed by Tyr366 and Tyr395. These results are discussed in terms of mechanism of GABAB activation promoted by baclofen or GABA.
QSAR and Molecular Modeling Studies of Baclofen Analogs as GABAB Agonists. Insights into the Role of the Aromatic Moiety in GABAB Binding and Activation / G. Costantino; A. Macchiarulo; A. Entrena Guadix; R. Pellicciari. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 1520-4804. - 44(2001), pp. 1827-1832. [10.1021/jm0100133]