1.Distinctive effects of nicotinic receptor intracellular-loop mutations associated with nocturnal frontal lobe epilepsy.
Weltzin MM1, Lindstrom JM2, Lukas RJ3, Whiteaker P4. Neuropharmacology. 2016 Mar;102:158-73. doi: 10.1016/j.neuropharm.2015.11.004. Epub 2015 Nov 10.
Previously characterized nicotinic acetylcholine receptor (nAChR) autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)-associated mutations are found in α2, α4 and β2 subunit transmembrane (TM) domains. They predominantly increase ACh potency and, for β2-subunit mutants, increase macroscopic currents. Two recently-identified mutations, α4(R336H) and β2(V337G), located in the intracellular cytoplasmic loop (C2) have been associated with non-familial NFLE. Effects of these mutations on α4β2-nAChR function and expression were studied for the first time, using two-electrode voltage clamp recordings in Xenopus laevis oocytes. Biased-ratio preparations elucidated the mutations' effects at alternate isoforms: high-sensitivity [HS; (α4)2(β2)3] or low-sensitivity [LS; (α4)3(β2)2] via 1:10 or 30:1 [α4:β2] cRNA injection ratios, respectively. An unbiased (1:1 [α4:β2] cRNA) injection ratio was also used to study potential shifts in isoform expression.
2.Cytisine-type alkaloids and flavonoids from the rhizomes of Sophora tonkinensis.
Pan QM1, Zhang GJ2, Huang RZ1, Pan YM1, Wang HS1, Liang D1. J Asian Nat Prod Res. 2016 May;18(5):429-35. doi: 10.1080/10286020.2015.1131680. Epub 2016 Jan 13.
A new cytisine-type alkaloid, (-)-N-hexanoylcytisine (1), and a new isoflavan, (3S, 4R)-4-hydroxy-7,4'-dimethoxyisoflavan 3'-O-β-d-glucopyranoside (2), along with 10 known compounds, were isolated from the rhizomes of Sophora tonkinensis. Their structures were determined by spectroscopic methods, chemical evidence, and ECD data analysis. All of the isolates were evaluated for their cytotoxic activities against four human tumor cell lines.
3.Neuronal Nicotinic Acetylcholine Receptor Modulators Reduce Sugar Intake.
Shariff M1, Quik M2, Holgate J1, Morgan M1, Patkar OL1, Tam V3, Belmer A1, Bartlett SE1. PLoS One. 2016 Mar 30;11(3):e0150270. doi: 10.1371/journal.pone.0150270. eCollection 2016.
Excess sugar consumption has been shown to contribute directly to weight gain, thus contributing to the growing worldwide obesity epidemic. Interestingly, increased sugar consumption has been shown to repeatedly elevate dopamine levels in the nucleus accumbens (NAc), in the mesolimbic reward pathway of the brain similar to many drugs of abuse. We report that varenicline, an FDA-approved nicotinic acetylcholine receptor (nAChR) partial agonist that modulates dopamine in the mesolimbic reward pathway of the brain, significantly reduces sucrose consumption, especially in a long-term consumption paradigm. Similar results were observed with other nAChR drugs, namely mecamylamine and cytisine. Furthermore, we show that long-term sucrose consumption increases α4β2 * and decreases α6β2* nAChRs in the nucleus accumbens, a key brain region associated with reward. Taken together, our results suggest that nAChR drugs such as varenicline may represent a novel treatment strategy for reducing sugar consumption.
4.Structure-based screening and optimization of cytisine derivatives as inhibitors of the menin-MLL interaction.
Zhong HJ1, Lee BR2, Boyle JW2, Wang W3, Ma DL3, Hong Chan PW4, Leung CH1. Chem Commun (Camb). 2016 Mar 23. [Epub ahead of print]
The natural product-like compound was identified as a direct inhibitor of the menin-MLL interaction by in silico screening. Structure-based optimization furnished analogue 1a, which showed significantly higher potency than both the lead structure 1 and the reference compound MI-2.