ABSTRACT
We investigated the anxiolytic effects and mechanism of action of a new anxiolytic drug, (R)-piperonyl-1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridine-3- carboxamide hydrochloride (AP521). AP521 showed equal or more potent anxiolytic-like effects compared with diazepam, a benzodiazepine receptor agonist, or tandospirone, a partial 5-hydroxytryptamine (5-HT)1A receptor agonist, in three rat anxiety models; the Vogel-type conflict test, elevated plus maze test, and conditioned fear stress test. Although AP521 did not bind to the benzodiazepine receptor, it did bind to 5-HT1A, 5-HT1B, 5-HT1D, 5-HT5A and 5-HT7 receptors, and showed agonist activity for the human 5-HT1A receptor expressed in HEK293 cells. Tandospirone, which can stimulate the presynaptic 5-HT1A receptors in the raphe, tended to decrease extracellular 5-HT concentration in the medial prefrontal cortex (mPFC) in rats. In contrast, AP521 increased extracellular 5-HT concentration. In addition, AP521 enhanced the anti-freezing effect of citalopram, a selective serotonin reuptake inhibitor, in the fear conditioning model in rats and enhanced the citalopram-caused increase of the extracellular 5-HT concentration in the mPFC. These results suggest that AP521 exhibits potent anxiolytic effects by acting as a postsynaptic 5-HT1A receptor agonist and by enhancing serotonergic neural transmission in the mPFC by a novel mechanism of action.
Subject(s)
Anti-Anxiety Agents/pharmacology , Pyridines/pharmacology , Serotonin/metabolism , Synaptic Transmission/drug effects , Thiophenes/pharmacology , Animals , Anti-Anxiety Agents/therapeutic use , Anxiety/drug therapy , Cells, Cultured , Citalopram/pharmacology , Diazepam/pharmacology , Disease Models, Animal , Drug Synergism , Humans , Isoindoles/pharmacology , Male , Piperazines/pharmacology , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Pyridines/therapeutic use , Pyrimidines/pharmacology , Rats , Receptors, Serotonin/metabolism , Serotonin 5-HT1 Receptor Agonists/pharmacology , Thiophenes/therapeutic useABSTRACT
A chiral five-membered ring α,α-disubstituted α-amino acid (R,R)-Ac5c(dN3) having two azido functional groups has been designed and synthesized. The cyclic amino acid (R,R)-Ac5c(dN3) could be efficiently converted into several cyclic amino acids with various two 1,2,3-triazole functional groups. (R,R)-Ac5c(dN3) homochiral peptides (up to hexapeptide) and (R,R)-Ac5c(dN3)-containing l-Leu-based peptides were prepared, and their conversion of azido functional groups into triazole groups was completed. The preferred conformation of oligomers, before and after the "click reaction", together with the azido gauche effect of amino acid residues were studied using FT-IR absorption, CD, (1)H NMR, and X-ray crystallographic analysis. The cyclic amino acid (R,R)-Ac5c(dN3) could be used as a helical conformation controlling residue and also has a versatile functionalizing site in its oligopeptides.
Subject(s)
Amino Acids, Cyclic/chemistry , Amino Acids/chemistry , Azides/chemistry , Peptides/chemistry , Triazoles/chemistry , Click Chemistry , Crystallography, X-Ray , Hydrogen Bonding , Magnetic Resonance Spectroscopy , Spectroscopy, Fourier Transform InfraredABSTRACT
An asymmetric synthesis of chiral intermediate 3 for (-)-oseltamivir phosphate has been accomplished from chiral building block 1, which was prepared by catalytic asymmetric synthesis.
