Abstract:
:Stereotypy (e.g., repetitive hand waving) is a key phenotype of autism spectrum disorder, Fragile X and Rett syndromes, and other neuropsychiatric disorders, and its severity correlates with cognitive and attention deficits. There are no effective treatments, however, for stereotypy. Perturbation of serotonin (5-HT) neurotransmission contributes to stereotypy, suggesting that distinct 5-HT receptors may be pharmacotherapeutic targets to treat stereotypy and related neuropsychiatric symptoms. For example, preclinical studies indicate that 5-HT7 receptor activation corrects deficits in mouse models of Fragile X and Rett syndromes, and clinical trials for autism are underway with buspirone, a 5-HT1A partial agonist with relevant affinity at 5-HT7 receptors. Herein, we report the synthesis, in vitro molecular pharmacology, behavioral pharmacology, and pharmacokinetic parameters in mice after subcutaneous and oral administration of (+)-5-(2'-fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine ((+)-5-FPT), a new, dual partial agonist targeting both 5-HT7 (Ki = 5.8 nM, EC50 = 34 nM) and 5-HT1A (Ki = 22 nM, EC50 = 40 nM) receptors. Three unique, heterogeneous mouse models were used to assess the efficacy of (+)-5-FPT to reduce stereotypy: idiopathic jumping in C58/J mice, repetitive body rotations in C57BL/6J mice treated with the NMDA antagonist, MK-801, and repetitive head twitching in C57BL/6J mice treated with the 5-HT2 agonist, DOI. Systemic (+)-5-FPT potently and efficaciously reduced or eliminated stereotypy in each of the mouse models without altering locomotor behavior on its own, and additional tests showed that (+)-5-FPT, at the highest behaviorally active dose tested, enhanced social interaction and did not cause behaviors indicative of serotonin syndrome. These data suggest that (+)-5-FPT is a promising medication for treating stereotypy in psychiatric disorders.
journal_name
ACS Chem Neuroscijournal_title
ACS chemical neuroscienceauthors
Canal CE,Felsing DE,Liu Y,Zhu W,Wood JT,Perry CK,Vemula R,Booth RGdoi
10.1021/acschemneuro.5b00099subject
Has Abstractpub_date
2015-07-15 00:00:00pages
1259-70issue
7issn
1948-7193journal_volume
6pub_type
杂志文章abstract::Dopamine (DA) is a neurotransmitter implicated in multiple functions, including movement, cognition, motivation, and reward. The DA transporter (DAT) is responsible for clearing extracellular DA, thereby terminating DA neurotransmission. Previously, it has been shown that insulin signaling through protein kinase B/Akt...
journal_title:ACS chemical neuroscience
pub_type: 信件
doi:10.1021/cn100031t
更新日期:2010-07-21 00:00:00
abstract::Baicalein, a flavonoid derived from the roots of Scutellariae baicalensis Georgi, has shown health benefits for an array of human diseases including dementia. The senescence-accelerated mouse prone 8 (SAMP8) strain is extensively used as a senile dementia model. To further investigate the effects of baicalein in SAMP8...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.8b00074
更新日期:2018-07-18 00:00:00
abstract::We report the results of computational modeling of a three-dimensional all-atom structure of the membrane-associated protein encoded by the NAT8L gene, aspartate N-acetyltransferase, which is essential for brain synthesis of N-acetyl-l-aspartate (NAA). The lack of experimentally derived three-dimensional structures of...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.0c00250
更新日期:2020-08-05 00:00:00
abstract::Azobenzenes are the most widely studied photoswitches, and have become popular optical probes for biological systems. The cis configuration is normally metastable, meaning the trans configuration is always thermodynamically favored. The unique exception to this rule is an azobenzene having a two-carbon bridge between ...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.8b00734
更新日期:2019-05-15 00:00:00
abstract::The melanocortin system regulates an array of diverse physiological functions including pigmentation, feeding behavior, energy homeostasis, cardiovascular regulation, sexual function, and steroidogenesis. Endogenous melanocortin agonist ligands all possess the minimal messaging tetrapeptide sequence His-Phe-Arg-Trp. B...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.8b00181
更新日期:2018-11-21 00:00:00
abstract::Of the free-living amoebae (FLA) Naegleria fowleri, Balamuthia mandrillaris, and Acanthamoeba spp. are known to cause encephalitis. Coined with the term "brain-eating amoebae" (BEA), infection of the central nervous system with FLA has a high mortality rate. A combination of diagnostic delay, lack of new drug developm...
journal_title:ACS chemical neuroscience
pub_type: 社论
doi:10.1021/acschemneuro.9b00635
更新日期:2020-08-19 00:00:00
abstract::Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder, with a 10% genetic linkage, of which 20% of these cases may be attributed to mutations in superoxide dismutase (SOD1). Specific mutations in SOD1 have been associated with disease duration, which can be highly variable ranging from a life...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.7b00140
更新日期:2017-10-18 00:00:00
abstract::We propose a tripartite mechanism to describe the processing of cognitive information (cog-info), comprising the (1) neuron, (2) surrounding neural extracellular matrix (nECM), and (3) numerous "trace" metals distributed therein. The neuron is encased in a polyanionic nECM lattice doped with metals (>10), wherein it p...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章,评审
doi:10.1021/cn300237r
更新日期:2013-06-19 00:00:00
abstract::Although there is no reported genetic predisposition in contracting coronavirus disease 2019 (COVID-19), the mortality rate varies among different ethnic groups. Here we determined potential correlation between COVID-19 and spice consumption. The data from 163 countries including total cases, total deaths, and total r...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.0c00239
更新日期:2020-06-17 00:00:00
abstract::Temozolomide (TMZ) is the current first-line chemotherapy for treatment of glioblastoma multiforme (GBM). However, similar to other brain therapeutic compounds, access of TMZ to brain tumors is impaired by the blood-brain barrier (BBB) leading to poor response for GBM patients. To overcome this major hurdle, we have s...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.8b00339
更新日期:2018-12-19 00:00:00
abstract::Serotonin (5-HT) is a key player in many physiological processes in both the adult organism and developing embryo. One of the mechanisms for 5-HT-mediated effects is covalent binding of 5-HT to the target proteins catalyzed by transglutaminases (serotonylation). Despite the implication in a variety of physiological pr...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.9b00346
更新日期:2019-08-21 00:00:00
abstract::When individual neurons in a circuit contain multiple neuropeptides, these peptides can target different sets of follower neurons. This endows the circuit with a certain degree of flexibility. Here we identified a novel family of peptides, the Aplysia SPTR-Gene Family-Derived peptides (apSPTR-GF-DPs). We demonstrated ...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.7b00513
更新日期:2018-08-15 00:00:00
abstract::Aggregation of hyperphosphorylated tau is the hallmark of several tauopathies, including Alzheimer's disease (AD). Although the mechanism underlying tau-associated neuronal damage remains unclear, it is believed that tau hyperphosphorylation is one of the key features in disease progression. A recent study demonstrate...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章,评审
doi:10.1021/acschemneuro.8b00632
更新日期:2019-01-16 00:00:00
abstract::Tropomyosin receptor kinases (TrkA/B/C) are critically involved in the development of the nervous system, in neurological disorders as well as in multiple neoplasms of both neural and non-neural origins. The development of Trk radiopharmaceuticals would offer unique opportunities toward a more complete understanding o...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/cn500193f
更新日期:2015-02-18 00:00:00
abstract::We propose a tripartite biochemical mechanism for memory. Three physiologic components are involved, namely, the neuron (individual and circuit), the surrounding neural extracellular matrix, and the various trace metals distributed within the matrix. The binding of a metal cation affects a corresponding nanostructure ...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/cn300097b
更新日期:2012-08-15 00:00:00
abstract::Neuronal cytotoxicity observed in Alzheimer's disease (AD) is linked to the aggregation of β-amyloid peptide (Aβ) into toxic forms. Increasing evidence points to oligomeric materials as the neurotoxic species, not Aβ fibrils; disruption or inhibition of Aβ self-assembly into oligomeric or fibrillar forms remains a via...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/cn100045q
更新日期:2010-09-15 00:00:00
abstract::The molecular mechanism of protein aggregation is of both fundamental and clinical importance as amyloid aggregates are linked to a number of neurodegenerative disorders. Such protein aggregates include macroscopic insoluble fibrils as well as small soluble oligomeric species. Time-dependent resolution of these specie...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.8b00250
更新日期:2018-12-19 00:00:00
abstract::The accumulation and deposition of fibrillar aggregates of α-synuclein (α-syn) into Lewy bodies are the major hallmarks of Parkinson's disease (PD) for which there is no cure yet. Disrupting preformed α-syn fibrils is considered one of the rational therapeutic strategies to combat PD. Experimental studies reported tha...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.0c00598
更新日期:2020-12-16 00:00:00
abstract::The delivery of specific genes into neurons offers a potent approach for treatment of diseases as well as for the study of neuronal cell biology. Here we investigated the capabilities of cationic amino acid based lipid assemblies to act as nonviral gene delivery vectors in primary cultured neurons. An arginine-based l...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/cn400036j
更新日期:2013-12-18 00:00:00
abstract::Parkinson's disease (PD) is the most widespread form of dementia where there is an age related degeneration of dopaminergic neurons in the substantia nigra region of the brain. Accumulation of α-synuclein (αS) protein aggregate, mitochondrial dysfunction, oxidative stress, and neuronal cell death are the pathological ...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.6b00207
更新日期:2016-12-21 00:00:00
abstract::The nonmedical (i.e., recreational) misuse of synthetic cannabinoids (SCs) is a worldwide public health problem. When compared to cannabis, the misuse of SCs is associated with a higher incidence of serious adverse effects, suggesting the possible involvement of noncannabinoid sites of action. Here, we find that, unli...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.0c00034
更新日期:2020-05-20 00:00:00
abstract::Pentameric glycine receptors (GlyRs) couple agonist binding to activation of an intrinsic ion channel. Substitution of the R271 residue impairs agonist-induced activation and is associated with the human disease hyperekplexia. On the basis of a homology model of the α1 GlyR, we substituted residues in the vicinity of ...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/cn400134p
更新日期:2013-11-20 00:00:00
abstract::Effective therapies for glioblastoma multiforme (GBM) are not currently available. A small molecule has been identified using fragment-based drug-discovery guided by NMR that targets important protein-protein interactions controlling GBM invasion and pathogenicity. This first generation drug displays excellent pharmac...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章,评审
doi:10.1021/acschemneuro.9b00016
更新日期:2019-03-20 00:00:00
abstract::Early diagnosis in Alzheimer's disease (AD), prior to the appearance of marked clinical symptoms, is critical to prevent irreversible neuronal damage and neural malfunction that lead to dementia and death. Therefore, there is an urgent need to generate new contrast agents which reveal by a noninvasive method the prese...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.7b00260
更新日期:2018-05-16 00:00:00
abstract::Inflammation is a potential factor in the pathophysiology of depression. A traditional Chinese herbal medicine, arctiin, and its aglycone, arctigenin, are the major bioactive components in Fructus arctii and exhibit neuroprotective and anti-inflammatory activities. Arctigenin has been reported to have antidepressant-l...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.0c00120
更新日期:2020-08-05 00:00:00
abstract::3-Iodobenzoyl naltrexamine (IBNtxA) is a potent analgesic belonging to the pharmacologically diverse 6β-amidoepoxymorphinan group of opioids. We present the synthesis and pharmacological evaluation of five analogs of IBNtxA. The scaffold of IBNtxA was modified by removing the 14-hydroxy group, incorporating a 7,8 doub...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.5b00153
更新日期:2015-11-18 00:00:00
abstract::Quaternary ammonium analogues of atropine that are unable to cross the blood-brain barrier are used to alleviate peripheral muscarinic toxicity in animal models of epilepsy produced by systemic administration of pilocarpine or diisopropylfluorophosphate (DFP). Currently, methylatropine is the most popular and potent o...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.6b00334
更新日期:2017-04-19 00:00:00
abstract::Single-cell mass spectrometry has become an established technique to study specific molecular properties such as the neuropeptide complement of identified neurons. Here, we describe a strategy to characterize, by MALDI-TOF mass spectrometry, neurochemical composition of neurons that were identified by their electrophy...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.8b00163
更新日期:2018-08-15 00:00:00
abstract::Neurons choose growth pathways with half hearted reluctance, behavior that may be appropriate to maintain fixed long lasting connections but not to regenerate them. We now recognize that intrinsic brakes on regrowth are widely expressed in these hesitant neurons and include classical tumor suppressor molecules. Here, ...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章,评审
doi:10.1021/cn500110p
更新日期:2014-08-20 00:00:00
abstract::The sensory nervous system controls cardiovascular homeostasis via capsaicin-sensitive neurons that release calcitonin gene-related peptide (CGRP), which subsequently activates CGRP receptors. How this perivascular CGRPergic discharge is modulated, nevertheless, remains unclear. In pithed rats, systemic vasodilation i...
journal_title:ACS chemical neuroscience
pub_type: 杂志文章
doi:10.1021/acschemneuro.9b00277
更新日期:2019-08-21 00:00:00