ABSTRACT
It is well known that 6-nitroquipazine exhibits about 150-fold higher affinity for the serotonin transporter (SERT) than quipazine and recently we showed quipazine buspirone analogues with high to moderate SERT affinity. Now we have designed and synthesized several 6-nitroquipazine buspirone derivatives. Unexpectedly, their SERT binding affinities were moderate, and much lower than that of the previously studied quipazine buspirone analogues. To explain these findings, docking studies of both groups of compounds into two different homology models of human SERT was performed using a flexible target-ligand docking approach (4D docking). The crystal structures of leucine transporter from Aquifex aeolicus in complex with leucine and with tryptophan were used as templates for the SERT models in closed and outward-facing conformations, respectively. We found that the latter conformation represents the most reliable model for binding of buspirone analogues. Docking into that model showed that the nitrated compounds acquire a rod like shape in the binding pocket with polar groups (nitro- and imido-) at the ends of the rod. 6-Nitro substituents gave steric clashes with amino acids located at the extracellular loop 4, which may explain their lower affinity than corresponding quipazine buspirone analogues. The results from the present study may suggest chemical design strategies to improve the SERT modulators.
Subject(s)
Buspirone/chemistry , Buspirone/pharmacology , Quipazine/analogs & derivatives , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin Plasma Membrane Transport Proteins/metabolism , Animals , Bacteria/chemistry , Bacteria/metabolism , Bacterial Proteins/chemistry , Bacterial Proteins/metabolism , Binding Sites , Buspirone/chemical synthesis , Humans , Models, Molecular , Piperazines/chemical synthesis , Piperazines/chemistry , Piperazines/pharmacology , Quipazine/chemical synthesis , Quipazine/chemistry , Quipazine/pharmacology , Serotonin Plasma Membrane Transport Proteins/chemistry , Selective Serotonin Reuptake Inhibitors/chemical synthesisABSTRACT
The reductive alkylation of amines procedure was applied for the synthesis of aripiprazole 1a, buspirone 1b, and NAN-190 1c.
Subject(s)
Amines/chemistry , Buspirone/chemical synthesis , Piperazines/chemical synthesis , Quinolones/chemical synthesis , Alkylation , Aripiprazole , Buspirone/chemistry , Chemistry Techniques, Synthetic/methods , Chromatography, High Pressure Liquid/methods , Hydrolysis , Molecular Structure , Oxidation-Reduction , Piperazines/chemistry , Quinolones/chemistry , Spectrometry, Mass, Electrospray Ionization/methodsABSTRACT
Three derivatives of 1,4 dichloro-dibenzo[e,h]-bicyclo[2.2.3]octane-2,3-dicarboximide were examined by 13C CPMAS NMR. Low energy conformations were found by a semi-empirical AM1 approach, NMR shielding constants were calculated using the GIAO RHF method.
Subject(s)
Anti-Anxiety Agents/chemistry , Buspirone/analogs & derivatives , Buspirone/chemistry , Magnetic Resonance Spectroscopy/methods , Anti-Anxiety Agents/chemical synthesis , Buspirone/chemical synthesis , Models, Molecular , Neural Networks, ComputerABSTRACT
A new analog of buspirone (1), i.e., 8-[4-[2-(1,2,3,4-tetrahydroisoquinolinyl)]butyl]-8-azaspiro- [4.5]decane-7,9-dione (6a), was synthesized. In was demonstrated that buspirone and its analog 6a were equipotent 5-HT(1A) ligands. Several behavioral models showed that 6a had essentially the same functional profile at 5-HT(1A) receptors as buspirone. The obtained results permit a conclusion that the basic nitrogen atom and terminal, bulky cycloimide moiety, but not the 2-pyrimidinyl group, of buspirone are directly involved in the formation of the bioactive complex with 5-Ht1A receptors.
