Neurotensin, a tridecapeptide, is widely distributed in the brain and gastrointestinal tract. It possesses analgesic, hypothermic, and antipsychotic-like properties. Neurotensin's effects are mediated mainly through two receptor subtypes, NTS1 and NTS2. Activation of NTS1 has been implicated in most of the pharmacological effects of neurotensin, but is associated with hypothermia and hypotension. We report on a novel neurotensin analog with higher selectivity to NTS2, namely, NT79 which exhibits selective behavioral effects.NT79 was tested in animal models for pain (thermal -hot plate test; visceral -acetic acid-induced writhing test), and in animal models that are predictive of antipsychotic-like effects (apomorphineinduced climbing; d-amphetamine-induced hyperactivity; disruption of prepulse inhibition). Its effects on body temperature and on blood pressure were also determined. Neurochemical changes in extracellular neurotransmitters were measured using in vivo microdialysis while the rats were simultaneously evaluated for acetic acid-induced writhing with and without pretreatment with NT79.Binding data at molecularly-cloned hNTS1 and hNTS2 suggest selectivity for hNTS2. NT79 blocked the acetic acid-induced writhing with an ED 50 of 0.14μg/kg, while having no effect on thermal nociception. The writhing was paralleled by an increase in 5-HT which was attenuated by NT79. NT79 demonstrated antipsychotic-like effects by blocking apomorphine-induced climbing, damphetamine-induced hyperactivity, and reducing d-amphetamine-and DOI-induced disruption of prepulse inhibition. Uniquely, it caused no significant hypothermia and was without effect on blood pressure. NT79, with its higher selectivity to NTS2, may be potentially useful to treat visceral pain, and psychosis without concomitant side effects of hypothermia or hypotension.
It remains a great challenge to develop polymer‐based materials with efficient and color‐tunable organic afterglow. Two indolocarbazole derivatives IaCzA and IbCzA have been synthesized and doped into poly(vinyl alcohol) (PVA) matrices. It is found that the resulting films can produce unique dual‐mode afterglow, which is composed of persistent thermally activated delayed fluorescence and ultralong organic phosphorescence. Besides, the IbCzA‐doped PVA film exhibits intense blue afterglow with Φafterglow and τafterglow up to 19.8 % and 1.81 s, respectively, representing state‐of‐the‐art dual‐mode organic afterglow performance. Moreover, our reported film has high flexibility, excellent transparency, and large‐area producibility; and the afterglow color of the film can be linearly tuned by temperature. Inspired by these distinctive properties, the PVA doped with IbCzA was employed as temperature‐sensitive security ink for anti‐counterfeiting and information encryption.
Aqueous sodium‐ion battery of low cost, inherent safety, and environmental benignity holds substantial promise for new‐generation energy storage applications. However, the narrow potential window of water and the enlarged ionic radius because of hydration restrict the selection of electrode materials used in the aqueous electrolyte. Here, inspired by the efficient redox reaction of biomolecules during cellular energy metabolism, a proof of concept is proposed that the redox‐active biomolecule alizarin can act as a novel electrode material for the aqueous sodium‐ion battery. It is demonstrated that the specific capacity of the self‐assembled alizarin nanowires can reach as high as 233.1 mA h g−1, surpassing the majority of anodes ever utilized in the aqueous sodium‐ion batteries. Paired with biocompatible and biodegradable polypyrrole, this full battery system shows excellent sodium storage ability and flexibility, indicating its potential applications in wearable electronics and biointegrated devices. It is also shown that the electrochemical properties of electrodes can be tailored by manipulating naturally occurring 9,10‐anthroquinones with various substituent groups, which broadens application prospect of biomolecules in aqueous sodium‐ion batteries.
Neurotensin (NT) is a tridecapeptide that acts as a neuromodulator in the central nervous system mainly through two NT receptors, NTS1 and NTS2. The functional-anatomical interactions between NT, the mesotelencephalic dopamine system, and structures targeted by dopaminergic projections have been studied. The present study was conducted to determine the effects of NT receptor subtypes on dopaminergic function with the use of mice lacking either NTS1 (NTS1−/−) or NTS2 (NTS2−/−). Basal and amphetamine-stimulated locomotor activity was determined. In vivo microdialysis in freely moving mice, coupled with HPLC-ECD, was used to detect basal and d-amphetamine-stimulated striatal extracellular dopamine levels. In vitro radioligand binding and synaptosomal uptake assays for the dopamine transporters were conducted to test for the expression and function of the striatal pre-synaptic dopamine transporter. NTS1−/− and NTS2−/− mice had higher baseline locomotor activity and higher basal extracellular dopamine levels in striatum. NTS1−/− mice showed higher locomotor activity and exaggerated dopamine release in response to d-amphetamine. Both NTS1−/− and NTS2−/− mice exhibited lower dopamine D1 receptor mRNA expression in the striatum relative to wild type mice. Dopamine transporter binding and dopamine reuptake in striatum were not altered. Therefore, lack of either NTS1 or NTS2 alters the dopaminergic system. The possibility that the dysregulation of dopamine transmission might stem from a deficiency in glutamate neurotransmission is discussed. The data strengthen the hypothesis that NT receptors are involved in the pathogenesis of schizophrenia and provide a potential model for the biochemical changes of the disease.
Three polyether-tethered berberine dimers (1a-c) were studied for their binding affinity, selectivity and thermal stabilization towards human telomeric dimeric quadruplex DNA (G2T1). Compound 1a with the shortest polyether linker showed the highest affinity (K > 10 M) and 76-508-fold higher selectivity for mixed-type G2T1 over antiparallel G2T1 and three monomeric G-quadruplexes, which are human telomeric monomeric quadruplex G1, c-kit 1 and c-kit 2. Compound 1a induced the formation of quadruplex structures and showed higher thermal stabilization for mixed-type G2T1 than for anti-parallel G2T1, G1 and ds DNA. Spectroscopic studies suggest that compound 1a could bind to mixed-type G2T1 via end-stacking and external binding modes. These results suggest that the polyether linkers in these compounds play an important role in regulating the binding affinity and selectivity towards mixed-type G2T1 and that compound 1a could target mixed-type G2T1 at other genome regions with antiparallel G2T1 and monomeric G-quadruplexes. These results may provide useful guidance for the rational design of selective multimeric G-quadruplex binders and potential anticancer agents.
Due to the putative involvement of dopaminergic circuits in depression, triple reuptake inhibitors are being developed as a new class of antidepressant, which is hypothesized to produce a more rapid onset and better efficacy than current antidepres-
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