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Treating neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) remains highly challenging. Noninvasive brain stimulation using repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) is of considerable interest in this context. To investigate the efficacy and safety of a novel technique involving simultaneous application of rTMS and tDCS (rTMS–tDCS) over bilateral angular gyrus (AG, P5/P6 electrode site) for AD-related NPS. Eighty-four AD patients were randomized to receive rTMS–tDCS, single-rTMS, single-tDCS, or sham stimulation for 4 weeks, with evaluation at week-4 (W4, immediately after treatment) and week-12 (W12, follow-up period) after initial examination. Primary outcome comprising Neuropsychiatric Inventory (NPI) score and secondary outcomes comprising mini-mental state examination (MMSE), AD assessment scale-cognitive subscale (ADAS-cog), and Pittsburgh sleep quality index (PSQI) scores were collected and analyzed by a two-factor (time and treatment), mixed-design ANOVA. rTMS–tDCS produced greater improvement in NPI scores than single-tDCS and sham at W4 and W12 (both P < 0.017) and trended better than single-rTMS (W4: P = 0.058, W12: P = 0.034). rTMS–tDCS improved MMSE scores compared with single-tDCS at W4 (P = 0.011) and sham at W4 and W12 (both P < 0.017). rTMS–tDCS also significantly improved PSQI compared with single-rTMS and sham (both P < 0.017). Interestingly, rTMS–tDCS-induced NPI/PSQI improvement was significantly associated with MMSE/ADAS-cog improvement. tDCS- and/or rTMS-related adverse events appeared slightly and briefly. rTMS–tDCS application to bilateral AG can effectively improve AD-related NPS, cognitive function, and sleep quality with considerable safety. • Simultaneous application of rTMS–tDCS in Alzheimer's Disease is safe and promising. • rTMS–tDCS produces greater improvement in neuropsychiatric symptoms than unimodal (tDCS or rTMS) and sham stimulation. • rTMS–tDCS achieves better effect on cognitive function, sleep quality than unimodal (tDCS or rTMS) and sham stimulation. • The improvements in NPS or sleep quality induced by rTMS–tDCS were significantly associated with cognitive improvement. [ABSTRACT FROM AUTHOR]

Abstract: Four series of novel heterodimers comprised of donepezil and huperzine A (HupA) fragments were designed, synthesized, and evaluated in search of potent acetylcholinesterase (AChE) inhibitors as potential therapeutic treatment for Alzheimer’s disease. Heterodimers comprised of dimethoxyindanone (from donepezil), hupyridone (from HupA), and connected with a multimethylene linker, were identified as potent and selective inhibitors of AChE. Diastereomeric heterodimers ( RS , S )-17b (with a tetramethylene linker) exhibited the highest potency of inhibition towards AChE with an IC50 value of 9nM and no detectable inhibitory effect on butyrylcholinesterase at 1mM. [Copyright &y& Elsevier]

Abstract: A series of novel and selective N-[3-(6-benzyloxy-3-methoxyphenyl)propyl] amides has recently been shown to possess sub-nanomolar range binding affinity to the type 2 melatonin receptor (MT2). Pharmacokinetics studies suggested that these compounds were subject to vigorous CYP450-mediated metabolism, resulting in a series of metabolites with significantly decreased or diminished binding affinities toward MT2 receptor. The ether bonds were found to be the major positions susceptible to metabolism. In this study, the benzyl ether bond was either removed or replaced with a carbon–carbon bond in an attempt to improve metabolic stability and enhance their resistance towards phase I oxidation. The synthesis, receptor binding affinity, intrinsic potency and metabolic stability of modified structures are reported in this article. By removal or replacement of metabolic labile ether linkerage with carbon linkers, a novel compound was identified with good potency and MT2 selectivity, and with increased metabolic stability. [Copyright &y& Elsevier]

Abstract: A series of substituted N-[3-(3-methoxyphenyl)propyl] amides were synthesized and their binding affinities towards human melatonin MT1 and MT2 receptors were evaluated. It was discovered that a benzyloxyl substituent incorporated at C6 position of the 3-methoxyphenyl ring dramatically enhanced the MT2 binding affinity and at the same time decreased MT1 binding affinity. [Copyright &y& Elsevier]

Highlights: [•] Nociceptive behaviors were increased in the UCMS group. [•] One of nociceptive behaviors correlated with depressive-like behaviors. [•] No significant differences were observed in the plasma level of CGRP and SP after stimulation. [•] The impact of depression on migraines probably does not depend on the peripheral afferent pathway. [Copyright &y& Elsevier]

Cholinergic neurons are ubiquitous and involved in various higher brain functions including learning and memory. Patients with Alzheimer's disease exhibit significant dysfunction and loss of cholinergic neurons. Meanwhile, such cholinergic deficits can be potentially relieved pharmacologically by increasing acetylcholine. Acetylcholinesterase (AChE) inhibitors have been used to improve cholinergic transmission in the brain for two decades and have proven effective for alleviating symptoms in the early stages of Alzheimer's disease. Therefore, the search for AChE inhibitors for drug development is ongoing. The enzymatic pocket of AChE has long been the target of several drug designs over the last two decades. The peripheral and catalytic sites of AChE are simultaneously bound by several dimeric molecules, enabling more-efficient inhibition. Here, we used 6-chlorotacrine and the tetrahydroquinolone moiety of huperzine A to design and synthesize a series of heterodimers that inhibit AChE at nanomolar potency. Specifically, compound 7b inhibits AChE with an IC 50 < 1 nM and spares butyrylcholinesterase. Administration of 7b to mouse brain slices restores synaptic activity impaired by pirenzepine, a muscarinic M1-selective antagonist. Moreover, oral administration of 7b to C57BL/6 mice enhances hippocampal long-term potentiation in a dose-dependent manner and is detectable in the brain tissue. All these data supported that 7b is a potential cognitive enhancer and is worth for further exploration. [Display omitted] • Design and synthesize tacrine-tetrahydroquinoline heterodimers that inhibit AChE. • 7b exhibits the highest potency and best toxicity ratio, with an IC 50 < 1 nM. • 7b shows the dual-binding property towards AChE. • 7b enhances hippocampal long-term potentiation in a dose-dependent manner. • 7b affects pathways involved in memory formation using transcriptomic analysis. [ABSTRACT FROM AUTHOR]

Development of structure–activity relationship of cyclic guanines I lead us to discovery of a potent and selective series of phosphodiesterase 5 inhibitors 52–59 (IC50=1.3–11.0 nM, PDE6/5=116–600). [Copyright &y& Elsevier]