QNZ 46

QNZ46 is a NR2C/NR2D-selective NMDA receptor non-competitive antagonist (IC50 values are 3, 6, 229, and >300, >300 μM for NR2D, NR2C, NR2A, NR2B, and GluR1, respectively). IC50 value: 3 μM (for NR2D), 6 μM (for NR2C), 229 μM (for NR2D NR2A) Target: NR2D, NR2C, NR2A in vitro: QNZ46 is a noncompetitive inhibitor of GluN2C/D containing NMDA receptors. KD and IC50 values for binding and inhibition of GluN1/Glun2D receptors by QNZ46 are 4.9 and 3.9 μM, respectively. QNZ46 does not compete for binding of glutamate or glycine, but QNZ46 receptor binding requires the binding of glutamate to the GluN2 subunit.

References:
[1]. Hansen KB, et al. Structural and mechanistic determinants of a novel site for noncompetitive inhibition of GluN2D-containing NMDA receptors. J Neurosci. 2011 Mar 9;31(10):3650-3661.

Complete Genome Sequence of Staphylococcus aureus Strain Wood 46.[Pubmed:28360163]

Genome Announc. 2017 Mar 30;5(13). pii: 5/13/e00087-17.

Here, we report the first complete genome sequence of the Staphylococcus aureus strain Wood 46. Wood 46 has played an important role in understanding the virulence and pathogenesis of S. aureus infections. This report will assist efforts in vaccine development against methicillin-resistant S. aureus (MRSA) infections.

Functional roles of T3.37 and S5.46 in the activation mechanism of the dopamine D1 receptor.[Pubmed:28361444]

J Mol Model. 2017 Apr;23(4):142.

The activation mechanism of dopamine receptors is unknown. The amino acids S5.42, S5.43, and S5.46 located in helix 5 appear to be crucial, but their specific roles in receptor activation have not been studied. We modeled the D1 dopamine receptor using the crystal structures of the D3 dopamine and beta2 adrenergic receptors. Molecular dynamics simulations show that the interaction of dopamine with the D1 receptor leads to the formation of a hydrogen-bond network with its catechol group and helices 3, 5, and 6, including water molecules. The para hydroxyl group of dopamine binds directly to S5.42 and N6.55, the latter also interacting with S5.43. Unexpectedly, S5.46 does not interact directly with the catechol; instead, it interacts through a water molecule with S5.42 and directly with T3.37. The formation of this hydrogen-bond network, part of which was previously observed in docking studies with dopamine agonists, triggers the opening of the E6.30-R3.60 ionic lock associated with the activation of GPCRs. These changes do not occur in the unbonded (apo) receptor or when it is in a complex with the antagonist 3-methoxy-5,6,7,8,9,14-hexahydrodibenz[d,g]azecine. Our results provide valuable insight into the T3.37-S5.46-water-S5.43-ligand interaction, which may be crucial to the activation of the D1 dopamine receptor and should be considered during the design of novel agonists. Graphical Abstract General representation of the relationship between the formation of the HBN and the opening of the R3.50-E6.30 ionic lock.

Ten cases with 46,XX testicular disorder of sex development: single center experience.[Pubmed:28379671]

Int Braz J Urol. 2017 Jul-Aug;43(4):770-775.

OBJECTIVE: To present clinical, chromosomal and hormonal features of ten cases with SRY-positive 46,XX testicular disorder of sex development who were admitted to our infertility clinic. CASES AND METHODS: Records of the cases who were admitted to our infertility clinic between 2004 and 2015 were investigated. Ten 46,XX testicular disorder of sex development cases were detected. Clinical, hormonal and chromosomal assessments were analized. RESULTS: Mean age at diagnosis was 30.4, mean body height was 166.9cm. Hormonal data indicated that the patients had a higher FSH, LH levels, lower TT level and normal E2, PRL levels. Karyotype analysis of all patients confirmed 46,XX karyotype, and FISH analysis showed that SRY gene was positive and translocated to Xp. The AZFa, AZFb and AZFc regions were absent in 8 cases. In one case AZFb and AZFc incomplete deletion and normal AZFa region was present. In the other one all AZF regions were present. CONCLUSION: Gonadal development disorders such as SRY-positive 46,XX testicular disorder of sex development can be diagnosed in infertility clinics during infertility workup. Although these cases had no chance of bearing a child, they should be protected from negative effects of testosterone deficiency by replacement therapies.

Structural and mechanistic determinants of a novel site for noncompetitive inhibition of GluN2D-containing NMDA receptors.[Pubmed:21389220]

J Neurosci. 2011 Mar 9;31(10):3650-61.

NMDA receptors are ionotropic glutamate receptors that mediate excitatory synaptic transmission and have been implicated in several neurological diseases. We have evaluated the mechanism of action of a class of novel subunit-selective NMDA receptor antagonists, typified by (E)-4-(6-methoxy-2-(3-nitrostyryl)-4-oxoquinazolin-3(4H)-yl)-benzoic acid (QNZ46). We found that QNZ46 inhibits NMDA receptor function in a noncompetitive and voltage-independent manner by an unconventional mechanism that requires binding of glutamate to the GluN2 subunit, but not glycine binding to the GluN1 subunit. This dependency of antagonist association on glutamate binding to GluN2 renders these compounds nominally use-dependent, since inhibition will rely on synaptic release of glutamate. Evaluation of the structural determinants responsible for the subunit-selectivity of QNZ46 revealed that these compounds act at a new site that has not previously been described. Residues residing in the part of the agonist binding domain immediately adjacent to the transmembrane helices appear to control selectivity of QNZ46 for GluN2C- and GluN2D-containing receptors. These residues are well-positioned to sense glutamate binding to GluN2 and thus to mediate glutamate-dependent actions. This new class of noncompetitive antagonists could provide an opportunity for the development of pharmacological tools and therapeutic agents that target NMDA receptors at a new site and modulate function by a novel mechanism.

Quinazolin-4-one derivatives: A novel class of noncompetitive NR2C/D subunit-selective N-methyl-D-aspartate receptor antagonists.[Pubmed:20684595]

J Med Chem. 2010 Aug 12;53(15):5476-90.

We describe a new class of subunit-selective antagonists of N-methyl D-aspartate (NMDA)-selective ionotropic glutamate receptors that contain the (E)-3-phenyl-2-styrylquinazolin-4(3H)-one backbone. The inhibition of recombinant NMDA receptor function induced by these quinazolin-4-one derivatives is noncompetitive and voltage-independent, suggesting that this family of compounds does not exert action on the agonist binding site of the receptor or block the channel pore. The compounds described here resemble CP-465,022 ((S)-3-(2-chlorophenyl)-2-[2-(6-diethylaminomethyl-pyridin-2-yl)-vinyl]-6-fluoro- 3H-quinazolin-4-one), a noncompetitive antagonist of AMPA-selective glutamate receptors. However, modification of ring substituents resulted in analogues with greater than 100-fold selectivity for recombinant NMDA receptors over AMPA and kainate receptors. Furthermore, within this series of compounds, analogues were identified with 50-fold selectivity for recombinant NR2C/D-containing receptors over NR2A/B containing receptors. These compounds represent a new class of noncompetitive subunit-selective NMDA receptor antagonists.

QNZ46 is a NR2C/NR2D-selective NMDA receptor non-competitive antagonist (IC50 values are 3, 6, 229, and >300, >300 μM for NR2D, NR2C, NR2A, NR2B, and GluR1, respectively).

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