Binding of Arylpiperazines, (Aryloxy)propanolamines, and Tetrahydropyridylindoles to the 5-HT_1A Receptor:  Contribution of the Molecular Lipophilicity Potential to Three-Dimensional Quantitative Structure−Affinity Relationship Models

Abstract

A set of 280 5-HT1A receptor ligands were selected from available literature data according to predefined criteria and subjected to three-dimensional quantitative structure-affinity relationship analysis using comparative molecular field analysis. No model was obtained for serotonin analogues (19 compounds) and aminotetralins (60 compounds), despite a variety of alignment hypotheses being tried. In contrast, the steric, electrostatic, and lipophilicity fields alone and in combination yielded informative models for arylpiperazines (101 training compounds and 12 test compounds), (aryloxy)propanolamines (30 training compounds and four test compounds), and tetrahydropyridylindoles (54 training compounds) taken separately (models A, B, and C). Arylpiperazines and (aryloxy)propanolamines were then combined successfully to yield reasonably good models for 131 compounds (model D). In a last step, the three chemical classes (185 compounds) were combined, again successfully (model E). This stepwise procedure not only ascertains self-consistency in alignments but it also allows statistical signals (i.e., favorable or unfavorable regions around molecules) to emerge which cannot exist in a single chemical class. The models so obtained reveal a number of interaction sites between ligands and the 5-HT1A receptor, and extend the information gathered from a model based on homology modeling.

A Three Binding Site Hypothesis for the Interaction of Ligands with Monoamine G Protein-coupled Receptors: Implications for Combinatorial Ligand Design

“…These alternative solutions might correspond to alternative binding modes which can ideally be supported by complementary model building studies of ligand-receptor complexes. A recent CoMFA analysis of the 5-HT 1A ligands documents such a situation [54]. The study revealed a single mode of interaction for arylpiperazines, aryloxypropanolamines and tetrahydropyrindoles at the 5-HT 1A receptor, whereas for serotonin and aminotetralines no single dominant binding model could be derived, which is indicative of the existence of alternative binding modes andyor of the inherent information poverty of the available data set [54].…”

“…A recent CoMFA analysis of the 5-HT 1A ligands documents such a situation [54]. The study revealed a single mode of interaction for arylpiperazines, aryloxypropanolamines and tetrahydropyrindoles at the 5-HT 1A receptor, whereas for serotonin and aminotetralines no single dominant binding model could be derived, which is indicative of the existence of alternative binding modes andyor of the inherent information poverty of the available data set [54]. The strikingly different results which are obtained for the superposition of three``double'' monoamine ligands corresponding to the three possible heterogeneous combinations of the constituting ligand fragments by either accepting à`t wo site'' or a``three site'' hypothesis are indicative of the dilemma of structural alignments for monoamine ligands.…”

Building a Bridge between G-Protein-Coupled Receptor Modelling, Protein Crystallography and 3D QSAR Studies for Ligand Design

“…Gaillard et al [63] an electron-rich region (Ser-199) close to nitrogen of the indole ring of tetrahydropyridylindoles. The receptor model also indicated that a large region was allowed for the nitrogen substituent between helices III, VI and VII.…”

Development of empirical molecular interaction models that incorporate hydrophobicity and hydropathy. The HINT paradigm

“…The most significant application of these maps, however, is that they can be imported into 3D QSAR programs such as CoMFA [32] as hydropathic/hydrophobic fields to supplement the standard complement of steric and electrostatic field types. Since we first reported the HINT/CoMFA interface numerous studies have been performed using HINT [33][34][35][36][37][38] as well as other lipophilic field models [39,40] with 3D QSAR. Our experience is mixed.…”