164166-95-4Relevant articles and documents
Reevaluating the Substrate Specificity of the L-Type Amino Acid Transporter (LAT1)
Chien, Huan-Chieh,Colas, Claire,Finke, Karissa,Springer, Seth,Stoner, Laura,Zur, Arik A.,Venteicher, Brooklynn,Campbell, Jerome,Hall, Colton,Flint, Andrew,Augustyn, Evan,Hernandez, Christopher,Heeren, Nathan,Hansen, Logan,Anthony, Abby,Bauer, Justine,Fotiadis, Dimitrios,Schlessinger, Avner,Giacomini, Kathleen M.,Thomas, Allen A.
, p. 7358 - 7373 (2018/08/06)
The L-type amino acid transporter 1 (LAT1, SLC7A5) transports essential amino acids across the blood-brain barrier (BBB) and into cancer cells. To utilize LAT1 for drug delivery, potent amino acid promoieties are desired, as prodrugs must compete with millimolar concentrations of endogenous amino acids. To better understand ligand-transporter interactions that could improve potency, we developed structural LAT1 models to guide the design of substituted analogues of phenylalanine and histidine. Furthermore, we evaluated the structure-activity relationship (SAR) for both enantiomers of naturally occurring LAT1 substrates. Analogues were tested in cis-inhibition and trans-stimulation cell assays to determine potency and uptake rate. Surprisingly, LAT1 can transport amino acid-like substrates with wide-ranging polarities including those containing ionizable substituents. Additionally, the rate of LAT1 transport was generally nonstereoselective even though enantiomers likely exhibit different binding modes. Our findings have broad implications to the development of new treatments for brain disorders and cancer.
Synthesis and in vitro pharmacology of a series of new chiral histamine H3-receptor ligands: 2-(R and S)-amino-3-(1H-imidazol-4(5)-yl)propyl ether derivatives
Kovalainen, Jari T.,Christiaans, Johannes A. M.,Kotisaari, Sanna,Laitinen, Jarmo T.,M?nnist?, Pekka T.,Tuomisto, Leena,Gynther, Jukka
, p. 1193 - 1202 (2007/10/03)
To investigate stereospecificity and the mechanism of activation of the histamine H3-receptor, a series of 2-(R and S)-amino-3-(1H-imidazol-4(5)- yl)propyl ether derivatives were synthesized. In these compounds, the structures of the well-known antagonist iodoproxyfan and the full agonists R- or S-(α)-methylhistamine were combined in one molecule. The obtained 'hybrid' molecules were tested for H3-receptor affinity on rat cerebral cortex. Some selected compounds were further screened for H3-receptor functional activity with GTPγ[35S] autoradiography studies using rat brain tissue sections. The affinity of all the synthesized compounds (-log K(i) = 5.9-7.9) was lower than that found for iodoproxyfan or two of its analogues; however, the compounds showed stereospecificity. The S-configuration of the series of 2-amino-3-(1H-imidazol-4(5)-yl)propyl ether derivatives, which resembles the stereochemistry of R-(α)-methylhistamine, was more favorable. Incorporation of an amino group in the propyl chain of iodoproxyfan and analogues did not alter the antagonistic behavior for compounds with an aromatic side chain. However, when also the aromatic moiety was replaced by a cyclohexyl group, the compounds behaved as agonists. This indicates that an interaction between the side chain amino group and the H3-receptor protein is involved in H3-receptor activation. The 2-(S)-amino-3-(1H-imidazol-4(5)- yl)propyl cyclohexylmethyl ether (23) has H3-receptor agonistic properties with high affinity for the histamine H3-receptor (-log K(i) = 7.9 ± 0.2) and might serve as a useful tool for further studies concerning drug design and receptor-ligand interactions.
Facile Preparation of the 1-Hydroxybenzotriazolyl Ester of N-Tritylpyroglutamic Acid and its Application to the Synthesis of TRH, 2>TRH and Analogues Incorporating cis- and trans-4-Hydroxy-L-proline
Papaioannou, Dionissios,Athanassopoulos, Constantinos,Magafa, Vassiliki,Karigiannis, George,Karamanos, Nikos,et al.
, p. 103 - 114 (2007/10/02)
One-pot treatment of N-trityl-L-glutamic acid with DCC followed by DCC-HOBt provided a high yielding synthesis of the 1-hydroxybenzotriazolyl ester of N-trityl-L-pyroglutamic acid (Trt-Glp). Coupling of this active ester with the methyl esters of Nim-tritylated L- and D-histidine provided the corresponding dipeptides which upon saponification and coupling with the methyl esters of L-proline and trans-4-hydroxy-L-proline (Hyp) gave the protected tripeptides Trt-Glp-L and D-His-(Nim-Trt)-Pro-OMe and Trt-Glp-L and D-His(Nim-Trt)-Hyp-OMe. Some 10percent of the epimeric (at the His residue) products were formed during this procedure. Sequential saponification and one-pot Mitsunobu-type intramolecular esterification of the latter tripeptides, followed by transesterification with MeOH, provided the corresponding tripeptides Trt-Glp-L and D-His(Nim-Trt)-cHyp-OMe with inversion of configuration at C-4 of the Hyp ring. The observed conformer ratios about the His-Pro amide for all of these tripeptides are discussed in terms of structural features. Detritylation with trifluoroacetic acid followed by ammonolysis completed the synthesis of TRH and its analogues Glp-D-His-Pro-NH2, Glp-L- and D-His-Hyp-NH2 and Glp-L- and -D-His-cHyp-NH2.
