TBPB

TBPB is an allosteric M1 mAChR agonist(EC50=289 nM) that regulates amyloid processing and produces antipsychotic-like activity in rats. IC50 value: 289 nM(EC50) [2] Target: M1 mAChR agonist in vitro: TBPB activates M(1) through an allosteric site rather than the orthosteric acetylcholine binding site, which is likely critical for its unprecedented selectivity. Whole-cell patch-clamp recordings demonstrated that activation of M(1) by TBPB potentiates NMDA receptor currents in hippocampal pyramidal cells but does not alter excitatory or inhibitory synaptic transmission, responses thought to be mediated by M(2) and M(4) [1]. in vivo: TBPB was efficacious in models predictive of antipsychotic-like activity in rats at doses that did not produce catalepsy or peripheral adverse effects of other mAChR agonists [1].

References:
[1]. Jones CK, et al. Novel selective allosteric activator of the M1 muscarinic acetylcholine receptor regulates amyloid processing and produces antipsychotic-like activity in rats. J Neurosci. 2008 Oct 8;28(41):10422-33. [2]. Miller NR, et al. Synthesis and SAR of analogs of the M1 allosteric agonist TBPB. Part II: Amides, sulfonamides and ureas--the effect of capping the distal basic piperidine nitrogen. Bioorg Med Chem Lett. 2008 Oct 15;18(20):5443-7.

I2/TBPB mediated oxidative reaction of N-tosylhydrazones with anilines: practical construction of 1,4-disubstituted 1,2,3-triazoles under metal-free and azide-free conditions.[Pubmed:25250817]

Org Lett. 2014 Oct 3;16(19):5108-11.

An efficient I2 (20 mol %)/TBPB mediated oxidative formal [4 + 1] cycloaddition of N-tosylhydrazones with anilines via C-N/N-N bond formation and S-N cleavage has been developed. This protocol represents a simple, general, and efficient approach for the construction of 1,2,3-triazoles under metal-free and azide-free conditions by utilizing a catalytic amount of I2.

Conserved regions of gonococcal TbpB are critical for surface exposure and transferrin iron utilization.[Pubmed:23836816]

Infect Immun. 2013 Sep;81(9):3442-50.

The transferrin-binding proteins TbpA and TBPB enable Neisseria gonorrhoeae to obtain iron from human transferrin. The lipoprotein TBPB facilitates, but is not strictly required for, TbpA-mediated iron acquisition. The goal of the current study was to determine the contribution of two conserved regions within TBPB to the function of this protein. Using site-directed mutagenesis, the first mutation we constructed replaced the lipobox (LSAC) of TBPB with a signal I peptidase cleavage site (LAAA), while the second mutation deleted a conserved stretch of glycine residues immediately downstream of the lipobox. We then evaluated the resulting mutants for effects on TBPB expression, surface exposure, and transferrin iron utilization. Western blot analysis and palmitate labeling indicated that the lipobox, but not the glycine-rich motif, is required for lipidation of TBPB and tethering to the outer membrane. TBPB was released into the supernatant by the mutant that produces TBPB LSAC. Neither mutation disrupted the transport of TBPB across the bacterial cell envelope. When these mutant TBPB proteins were produced in a strain expressing a form of TbpA that requires TBPB for iron acquisition, growth on transferrin was either abrogated or dramatically diminished. We conclude that surface tethering of TBPB is required for optimal performance of the transferrin iron acquisition system, while the presence of the polyglycine stretch near the amino terminus of TBPB contributes significantly to transferrin iron transport function. Overall, these results provide important insights into the functional roles of two conserved motifs of TBPB, enhancing our understanding of this critical iron uptake system.

The genes that encode the gonococcal transferrin binding proteins, TbpB and TbpA, are differentially regulated by MisR under iron-replete and iron-depleted conditions.[Pubmed:27353397]

Mol Microbiol. 2016 Oct;102(1):137-51.

Neisseria gonorrhoeae produces two transferrin binding proteins, TbpA and TBPB, which together enable efficient iron transport from human transferrin. We demonstrate that expression of the tbp genes is controlled by MisR, a response regulator in the two-component regulatory system that also includes the sensor kinase MisS. The tbp genes were up-regulated in the misR mutant under iron-replete conditions but were conversely down-regulated in the misR mutant under iron-depleted conditions. The misR mutant was capable of transferrin-iron uptake at only 50% of wild-type levels, consistent with decreased tbp expression. We demonstrate that phosphorylated MisR specifically binds to the TBPBA promoter and that MisR interacts with five regions upstream of the TBPB start codon. These analyses confirm that MisR directly regulates TBPBA expression. The MisR binding sites in the gonococcus are only partially conserved in Neisseria meningitidis, which may explain why TBPBA was not MisR-regulated in previous studies using this related pathogen. This is the first report of a trans-acting protein factor other than Fur that can directly contribute to gonococcal TBPBA regulation.

tert-Butyl peroxybenzoate (TBPB)-mediated 2-isocyanobiaryl insertion with 1,4-dioxane: efficient synthesis of 6-alkyl phenanthridines via C(sp3)-H/C(sp2)-H bond functionalization.[Pubmed:24699898]

Chem Commun (Camb). 2014 Jun 21;50(49):6439-42.

An efficient method for the construction of 6-alkyl phenanthridines by tert-butyl peroxybenzoate (TBPB)-mediated 2-isocyanobiaryl insertion with 1,4-dioxane was established. Two new C-C bonds were formed in this reaction via a sequential C(sp(3))-H/C(sp(2))-H bond functionalization under metal-free conditions.

TBPB is an allosteric M1 mAChR agonist(EC50=289 nM) that regulates amyloid processing and produces antipsychotic-like activity in rats.

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