Although several therapeutic agents are available to aid in tobacco smoking cessation, relapse rates continue to be high, warranting the development of alternative pharmacotherapies. Nicotine-evoked ...dopamine release from its presynaptic terminals in the central nervous system leads to reward which maintains continued tobacco use. The ability of indolizidine (-)-235B' and a sub-library of structurally related analogs to inhibit nicotine-evoked super3Hdopamine release from rat striatal slices was determined in the current study. Indolizidine (-)-235B' inhibited nicotine-evoked super3Hdopamine release in a concentration-dependent manner (IC sub(50 = 42 nM, I) sub(m)ax = 55%). Compound (-)-237D, the double bond-reduced analog, afforded the greatest inhibitory potency (IC sub(50 = 0.18 nM, I) sub(m)ax = 76%), and was 233-fold more potent than indolizidine (-)-235B'. The des-8-methyl aza-analog of indolizidine (-)-235B', ZZ-272, also inhibited nicotine-evoked super3Hdopamine release (IC sub(50 = 413 nM, I) sub(m)ax = 59%). Concomitant exposure to maximally effective concentrations of indolizidine (-)-235B', ZZ-272 or (-)-237D with a maximally effective concentration of alpha -conotoxin MII, a selective antagonist for alpha 6 beta 2-containing nicotinic receptors, resulted in inhibition of nicotine-evoked super3Hdopamine release no greater than that produced by each compound alone. The latter results suggest that indolizidine (-)-235B', (-)-237D, ZZ-272 and alpha -conotoxin MII inhibit the same alpha -conotoxin MII-sensitive nicotinic receptor subtypes. Thus, indolizidine (-)-235B' and its analogs act as antagonists of alpha 6 beta 2-nicotinic receptors and constitute a novel structural scaffold for the discovery of pharmacotherapies for smoking cessation.
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Arylation of nitromethane with fluoroquinolones have been achieved through an S
NAr reaction under mild conditions in excellent yield. Subsequently the nitromethyl derivatives ...obtained were readily transformed into the corresponding aryl aldehyde, overall as an equivalent process of nucleophilic formylation.
Application of the nonadiabatic molecular dynamics (NAMD) approach is severely limited to studying carrier dynamics in the momentum space, since a supercell is required to sample the phonon ...excitation and electron-phonon (e-ph) interaction at different momenta in a molecular dynamics simulation. Here, we develop an ab initio approach for the real-time quantum dynamics for charge carriers in the momentum space (NAMD_k) by directly introducing the e-ph coupling into the Hamiltonian based on the harmonic approximation. The NAMD_k approach maintains the quantum zero-point energy and proper phonon dispersion, and includes memory effects of phonon excitation. The application of NAMD_k to the hot carrier dynamics in graphene reveals the phonon-specific relaxation mechanism. An energy threshold of 0.2eV, defined by two optical phonon modes strongly coupled to the electrons, separates the hot electron relaxation into fast and slow regions with the lifetimes of pico- and nano-seconds, respectively. The NAMD_k approach provides a powerful tool to understand real-time carrier dynamics in the momentum space for different materials.
Discriminating human-induced vegetation change is essential for sustainable managements of arid and semi-arid ecosystems. Residual Trends method (RESTREND), an effective quantitative method, has been ...widely used to discriminate human-induced vegetation changes in specific arid and semi-arid ecosystems. However, how to define homogeneous spatial neighborhood to determine reference pixel for estimating potential climate-solely-induced vegetation growth is still a challenge. This paper firstly detected vegetation dynamics in ArHorqin Banner of China from 2000 to 2014 by Mann-Kendall method, and then used RESTREND to profile human-induced changes. We optimized strategy in RESTREND by using statistical analysis and trajectory analysis to automatically define flexible homogeneous neighborhood. Results indicated that 18.6% of study area had significantly changes. Both climate change and human activities contributed to the changes. The influence of human activities on vegetation dynamics is more than climate change, and it was the main driver for vegetation decrease in study area.
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