Mapping and Fitting the Peripheral Benzodiazepine Receptor Binding Site by Carboxamide Derivatives. Comparison of Different Approaches to Quantitative Ligand−Receptor Interaction Modeling

The synthetic-computational approach to the study of the binding site of peripheral benzodiazepine receptor (PBR) ligands related to 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK11195, 1) within their receptor (Cappelli et al. J. Med. Chem. 1997, 40, 2910−2921) has bee...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 44; no. 8; pp. 1134 - 1150
Main Authors:	Anzini, Maurizio, Cappelli, Andrea, Vomero, Salvatore, Seeber, Michele, Menziani, Maria Cristina, Langer, Thierry, Hagen, Bertram, Manzoni, Cristina, Bourguignon, Jean-Jacques
Format:	Journal Article
Language:	English
Published:	Washington, DC American Chemical Society 12-04-2001
Subjects:	Amino Acid Sequence Animals Binding, Competitive Biological and medical sciences Cerebral Cortex - metabolism Gabaergic and benzodiazepinic system In Vitro Techniques Isoquinolines - chemistry Isoquinolines - metabolism Ligands Male Medical sciences Models, Molecular Molecular Conformation Molecular Sequence Data Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Pharmacology. Drug treatments Quantitative Structure-Activity Relationship Quinolines - chemical synthesis Quinolines - chemistry Quinolines - metabolism Radioligand Assay Rats Receptors, GABA-A - chemistry Receptors, GABA-A - metabolism Sequence Alignment Peripheral benzodiazepine receptor Nitrogen heterocycle Comparative molecular similarity Indices method Quinoline derivatives Binding site In vitro Modeling Three dimensional model Structure activity relation Correlation analysis Molecular model Tertiary amine Bicyclic compound Comparative molecular field analysis method Carboxamide Aromatic compound Chemical synthesis
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Summary:	The synthetic-computational approach to the study of the binding site of peripheral benzodiazepine receptor (PBR) ligands related to 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK11195, 1) within their receptor (Cappelli et al. J. Med. Chem. 1997, 40, 2910−2921) has been extended. A series of carboxamide derivatives endowed with differently substituted planar aromatic or heteroaromatic systems was designed with the aim of getting further information on the topological requisites of the carbonyl and aromatic moieties for interaction with the PBR binding site. The synthesis of most of these compounds involves Weinreb amidation of the appropriate lactone as the key step. The most potent compound, among the newly synthesized ones, shows a nanomolar PBR affinity similar to that shown by 1 and the presence of a basic N-ethyl-N-benzylaminomethyl group in 3-position of the quinoline nucleus. Thus, it may be considered the first example of a new class of water soluble derivatives of 1. Several computational methods were used to furnish descriptors of the isolated ligands (indirect approaches) able to rationalize the variation in the binding affinity of the enlarged series of compounds. Sound QSAR models are obtained by size and shape descriptors (volume approach) which codify for the short-range contributions to ligand−receptor interactions. Molecular descriptors which explicitly account for the electrostatic contribution to the interaction (CoMFA, CoMSIA, and surface approaches) perform well, but they do not improve the quantitative models. Moreover, useful hints for the identification of the antagonist binding site in the three-dimensional modeling of the receptor (direct approach) were provided by the receptor hypothesis derived by the pharmacophoric approach. The ligand−receptor complexes obtained provided a detailed description of the modalities of the interaction and interesting suggestions for further experiments.
Bibliography:	ark:/67375/TPS-WG2J6KZV-T istex:B14F29C81499E1190F21296561FB835D9435F393 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm0009742