Abstract:γ-Hydroxybutyric acid (GHB) is a neuroactive substance with specific high-affinity binding sites. To facilitate target identification and ligand optimization, we herein report a comprehensive structure-affinity relationship study for novel ligands targeting these binding sites. A molecular hybridization strategy was used based on the conformationally restricted 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA) and the linear GHB analog trans-4-hydroxycrotonic acid (T-HCA). In general, all structural modificatio… Show more
“…There has been much interest in comparing the structures of the ligands inside a receptor/protein with those of the free molecules, both determined by X-ray crystallography. While the X-ray geometry usually, as in the present case, matches the minimum-energy geometry calculated theoretically (both after optimization which relaxes the geometry), the geometry of the small molecule within the receptor only coincides in some cases; in others it differs by as much as 40 kJ mol À1 (Boströ m et al, 1998;Perola & Charifson, 2004;Fu et al, 2011;Sitzmann et al, 2012;Krall et al, 2017;Hawkins, 2017). Therefore, it is reasonable to assume that they act on the same receptor.…”
J147 [N-(2,4-dimethylphenyl)-2,2,2-trifluoro-N'-(3-methoxybenzylidene)acetohydrazide] has recently been reported as a promising new drug for the treatment of Alzheimer's disease. The X-ray structures of seven new 1,4-diaryl-5-trifluoromethyl-1H-1,2,3-triazoles, namely 1-(3,4-dimethylphenyl)-4-phenyl-5-trifluoromethyl-1H-1,2,3-triazole (CHFN, 1), 1-(3,4-dimethylphenyl)-4-(3-methoxyphenyl)-5-trifluoromethyl-1H-1,2,3-triazole (CHFNO, 2), 1-(3,4-dimethylphenyl)-4-(4-methoxyphenyl)-5-trifluoromethyl-1H-1,2,3-triazole (CHFNO, 3), 1-(2,4-dimethylphenyl)-4-(4-methoxyphenyl)-5-trifluoromethyl-1H-1,2,3-triazole (CHFNO, 4), 1-[2,4-bis(trifluoromethyl)phenyl]-4-(3-methoxyphenyl)-5-trifluoromethyl-1H-1,2,3-triazole (CHFNO, 5), 1-(3,4-dimethoxyphenyl)-4-(3,4-dimethoxyphenyl)-5-trifluoromethyl-1H-1,2,3-triazole (CHFNO, 6) and 3-[4-(3,4-dimethoxyphenyl)-5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenol (CHFNO, 7), have been determined and compared to that of J147. B3LYP/6-311++G(d,p) calculations have been performed to determine the potential surface and molecular electrostatic potential (MEP) of J147, and to examine the correlation between hydrazone J147 and the 1,2,3-triazoles, both bearing a CF substituent. Using MEPs, it was found that the minimum-energy conformation of 4, which is nearly identical to its X-ray structure, is closely related to one of the J147 seven minima.
“…There has been much interest in comparing the structures of the ligands inside a receptor/protein with those of the free molecules, both determined by X-ray crystallography. While the X-ray geometry usually, as in the present case, matches the minimum-energy geometry calculated theoretically (both after optimization which relaxes the geometry), the geometry of the small molecule within the receptor only coincides in some cases; in others it differs by as much as 40 kJ mol À1 (Boströ m et al, 1998;Perola & Charifson, 2004;Fu et al, 2011;Sitzmann et al, 2012;Krall et al, 2017;Hawkins, 2017). Therefore, it is reasonable to assume that they act on the same receptor.…”
J147 [N-(2,4-dimethylphenyl)-2,2,2-trifluoro-N'-(3-methoxybenzylidene)acetohydrazide] has recently been reported as a promising new drug for the treatment of Alzheimer's disease. The X-ray structures of seven new 1,4-diaryl-5-trifluoromethyl-1H-1,2,3-triazoles, namely 1-(3,4-dimethylphenyl)-4-phenyl-5-trifluoromethyl-1H-1,2,3-triazole (CHFN, 1), 1-(3,4-dimethylphenyl)-4-(3-methoxyphenyl)-5-trifluoromethyl-1H-1,2,3-triazole (CHFNO, 2), 1-(3,4-dimethylphenyl)-4-(4-methoxyphenyl)-5-trifluoromethyl-1H-1,2,3-triazole (CHFNO, 3), 1-(2,4-dimethylphenyl)-4-(4-methoxyphenyl)-5-trifluoromethyl-1H-1,2,3-triazole (CHFNO, 4), 1-[2,4-bis(trifluoromethyl)phenyl]-4-(3-methoxyphenyl)-5-trifluoromethyl-1H-1,2,3-triazole (CHFNO, 5), 1-(3,4-dimethoxyphenyl)-4-(3,4-dimethoxyphenyl)-5-trifluoromethyl-1H-1,2,3-triazole (CHFNO, 6) and 3-[4-(3,4-dimethoxyphenyl)-5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenol (CHFNO, 7), have been determined and compared to that of J147. B3LYP/6-311++G(d,p) calculations have been performed to determine the potential surface and molecular electrostatic potential (MEP) of J147, and to examine the correlation between hydrazone J147 and the 1,2,3-triazoles, both bearing a CF substituent. Using MEPs, it was found that the minimum-energy conformation of 4, which is nearly identical to its X-ray structure, is closely related to one of the J147 seven minima.
Chiral bridged [2,2,1] bicyclic lactones are privileged structural units in pharmaceutics and bioactive nature products. However, the synthetic methods for these compounds are rare. Here we report an efficient method for enantioselective construction of bridged [2,2,1] bicyclic lactones bearing a quaternary stereocenter via Rh-catalyzed asymmetric hydroformylation/intramolecular cyclization/pyridium chlorochromate (PCC) oxidation. By employing a hybrid phosphine-phosphite chiral ligand, a series of cyclopent-3-en-1-ols are transformed into corresponding γ-hydroxyl aldehydes with specific syn-selectivity. Then, hemiacetals form in situ and oxidation with PCC in one-pot affords bridged [2,2,1] bicyclic lactones in high yields and excellent enantiomeric excess. Replacing the hydroxyl group by an ester group, cyclopentanecarbaldehydes with a chiral all-carbon quaternary stereocenter in the γ-position can be generated efficiently.
“…; Krall et al . ) and the MCT1/2 inhibitor AR‐C141990 (( R )‐5‐(3‐hydroxypyrrolidine‐1‐carbonyl)‐1‐isobutyl‐3‐methyl‐6‐(quinolin‐4‐ylmethyl)thieno[2,3‐ d ]pyrimidine‐2,4(1 H ,3 H )‐dione), which was synthesized as described previously (Thiesen et al . ).…”
γ‐Hydroxybutyric acid (GHB) is an endogenous compound proposed to act as a neurotransmitter. Na+‐dependent, high‐affinity GHB transport has long been considered important evidence supporting this hypothesis. However, the molecular identity of such a high‐affinity transporter remains unknown. In this study, we sought to identify and characterize GHB synaptic transport through a series of studies using both native and recombinant systems with the ultimate aim of providing evidence to clarify the proposed role of GHB as a neurotransmitter in the mammalian brain. Native [3H]GHB transport was studied in isolated rat brain synaptosomes and compared to synaptic membranes. As a targeted approach, GHB was also screened against a panel of Na+‐dependent SLC6 neurotransmitter transporters recombinantly expressed in Xenopus laevis oocytes or tsA201 cells. Finally, the low‐affinity GHB transporters, MCT1/2 and SMCT1, were probed as GHB transporters in L‐[14C]lactate uptake assays in synaptosomes. We found no evidence of high‐affinity [3H]GHB transport in purified rat brain cortical or striatal synaptosomes or at any of the 11 SLC6 transporters tested. Instead, our results indicate the binding of [3H]GHB to an unidentified membrane component, distinct from any of the known GHB targets. In accordance with others, we found that GHB and the analog 3‐hydroxycyclopent‐1‐enecarboxylic acid (HOCPCA) can, in millimolar concentrations, inhibit L‐[14C]lactate uptake at MCT1 and/or MCT2 and that this also can occur in synaptosomes. In conclusion, through a variety of in vitro pharmacological studies, we were unsuccessful in identifying a specific synaptic high‐affinity transporter for GHB. Our findings emphasize the need to reevaluate GHB's role as a potential neurotransmitter.
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