Potential antidepressants and inhibitors of 5-hydroxytryptamine and noradrenaline re-uptake in the brain: N,N-Dimethyl-(arylthio)thenylamines and N,N-dimethyl-2-(thienylthio)benzylamines

1991 ◽  
Vol 56 (2) ◽  
pp. 449-458 ◽  
Author(s):  
Karel Šindelář ◽  
Josef Pomykáček ◽  
Martin Valchář ◽  
Karel Dobrovský ◽  
Jiřina Metyšová ◽  
...  
Keyword(s):  
Carboxylic Acid ◽  
Benzoic Acid ◽  
Potent Inhibitor ◽  
Brain Structures ◽  
Similar Type ◽  
Hydroxyl Group ◽  
Acid Chlorides ◽  
Selective Inhibitors ◽  
The Brain

3-(3-Methoxyphenylthio)thiophene-2-carboxylic acid (IV) and 2-(3-methoxyphenylthio)thiophene-3-carboxylic acid (VII) were transformed via acid chlorides and dimethylamides to the amines V and VIII which were demethylated to the phenolic amines VI and IX. N,N-Dimethyl-4-bromothiophene-3-carboxamide (XI) was reacted with 3-methoxythiophenol and the amide XII was reduced and demethylated to the amine XIV. 2-(2-Thienylthio)benzoic acid (XVa) and 2-(5-bromo-2-thienylthio)benzoic acid (XVb) were transformed via the isolated acid chlorides and N,N-dimethylamides to the amines XVIIIa and XVIIIb. The amines VI, IX, and XIV are thiophene isosters of moxifetin, the potent inhibitor of 5-hydroxytryptamine re-uptake in the brain structures. Out of the compounds prepared, only the methoxy amine VIII (VUFB-17697) showed a similar type of activity. The intermediate V, the phenolic amine VI, and the hydroxyl group lacking amine XVIIIa are selective inhibitors of noradrenaline re-uptake in the brain.

Potential antidepressants and selective inhibitors of 5-hydroxytryptamine re-uptake in the brain: Synthesis of several potential metabolites of moxifetin and of two A-ring fluorinated analogues

1991 ◽  
Vol 56 (2) ◽  
pp. 459-477 ◽  
Author(s):  
Karel Šindelář ◽  
Josef Pomykáček ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
Martin Valchář ◽  
...  
Keyword(s):  
Hydrobromic Acid ◽  
Methanesulfonic Acid ◽  
Brain Structures ◽  
Hydroxyl Group ◽  
Acid Chlorides ◽  
Selective Inhibitors ◽  
Mixed Anhydrides ◽  
The Brain ◽  
Short Heating ◽  
Acid Compound

A series of potential metabolites of the potent inhibitor of 5-hydroxytryptamine re-uptake in the brain structures – moxifetin (I) – i.e. the O-methylated and hydroxylated, further methoxylated, and N-monodemethylated analogues (III – VII, IX, and X) was synthesized from the acids XV, XIX, XXIIIa, XXIIIb, XXVIIa, and XXVIIb. The synthesis of III and V proceeded with protection of one hydroxyl group by benzyl and by the final debenzylation by short heating with hydrobromic acid. Compound IV was obtained by partial demethylation of N,N-dimethyl-(3-,4-dimethoxyphenylthio)benzylamine with sodium 4-toluenethiolate. Synthesis of VI, VII, IX, and X proceeded without protection of the hydroxyl group via the mixed anhydrides of the mentioned acids and methanesulfonic acid which were coupled with dimethylamine and the dimethylamides obtained were directly reduced to the final products. Two A-ring fluorinated analogues of I, i.e. VIII and XI were prepared from the acids XXIIIc and XXVIIc via acid chlorides, dimethylamides, and amines XXVIc and XXXc. The final step was demethylation by heating with hydrobromic acid. The N-oxide XII was obtained by oxidation of I with hydrogen peroxide in ethanol. Compounds III (VUFB-18285) and especially XI (VUFB-17724) were found to be selective inhibitors of the 5-hydroxytryptamine re-uptake in the brain. Some compounds (IV, VI, VII, X) indicate a similar type of activity. In addition to II (described previously), compounds IV and V were found to be moxifetin metabolites in the animals.

Potential antidepressants: 2-(Methoxy- and hydroxyphenylthio)benzylamines as selective inhibitors of 5-hydroxytryptamine re-uptake in the brain

1989 ◽  
Vol 54 (12) ◽  
pp. 3294-3338 ◽  
Author(s):  
Jiří Jílek ◽  
Karel Šindelář ◽  
Josef Pomykáček ◽  
Vojtěch Kmoníček ◽  
Zdeněk Šedivý ◽  
...  
Keyword(s):  
Brain Structures ◽  
Preclinical Studies ◽  
Lithium Aluminium Hydride ◽  
Selective Inhibitors ◽  
Highly Active ◽  
Lithium Aluminium ◽  
Boron Tribromide ◽  
Interesting Compound ◽  
Benzoyl Chlorides ◽  
The Brain

2-, 3- and 4Methoxythiophenol, and 2,4-, 2,5- and 3,4-dimethoxythiophenol were transformed in two steps to the corresponding 2-(methoxyphenylthio)benzoyl chlorides XIII which were reacted with ammonia, methylamine, diethylamine, dipropylamine, and di(2-propyl)amine to give the amides XIV-XIX. These were reduced mostly with lithium aluminium hydride to the amines II-VII. These methoxylated amines were demethylated mostly either by heating with pyridine hydrochloride or by treatment with boron tribromide. Some of the 2-(methoxy- and hydroxy-phenylthio)benzylamines prepared, especially compounds II, III, XXI, and XXII, indicated properties of potential antidepressants being highly active and selective inhibitors of 5-hydroxytryptamine re-uptake in the brain structures and having the typical antireserpine activity. The most interesting compound of the series is XXIb (hydrogen maleate VUFB-15 468) which is undergoing preclinical studies. On the basis of its structure, some further compounds (XXVII–XXIX, XXXIX-XLI) were prepared by various methods.

Fibrinolytic Activity of Cerebro-Spinal Fluid and the Development of Artificial Cerebral Haematomas in Dogs

1969 ◽  
Vol 21 (02) ◽  
pp. 294-303 ◽  
Author(s):  
H Mihara ◽  
T Fujii ◽  
S Okamoto
Keyword(s):  
Cerebrospinal Fluid ◽  
Carboxylic Acid ◽  
Fibrinolytic Activity ◽  
Clinical Implications ◽  
Trans Form ◽  
Plate Method ◽  
Blood Samples ◽  
Fibrin Plate ◽  
The Brain

SummaryBlood was injected into the brains of dogs to produce artificial haematomas, and paraffin injected to produce intracerebral paraffin masses. Cerebrospinal fluid (CSF) and peripheral blood samples were withdrawn at regular intervals and their fibrinolytic activities estimated by the fibrin plate method. Trans-form aminomethylcyclohexane-carboxylic acid (t-AMCHA) was administered to some individuals. Genera] relationships were found between changes in CSF fibrinolytic activity, area of tissue damage and survival time. t-AMCHA was clearly beneficial to those animals given a programme of administration. Tissue activator was extracted from the brain tissue after death or sacrifice for haematoma examination. The possible role of tissue activator in relation to haematoma development, and clinical implications of the results, are discussed.

Investigation of 2-Fluoro Benzoic Acid Derivatives as Influenza A Viral Sialidase Selective Inhibitors

2010 ◽  
Vol 9 (4) ◽  
pp. 198-204 ◽  
Author(s):  
Sadagopan Magesh ◽  
Nongluk Sriwilaijaroen ◽  
Vats Savita ◽  
Hiromune Ando ◽  
Taeko Miyagi ◽  
...  
Keyword(s):  
Benzoic Acid ◽  
Influenza A ◽  
Selective Inhibitors ◽  
Benzoic Acid Derivatives

Substituted N,N-Dimethyl-3-(phenylthio)- and -4-(phenylthio)benzylamines

1992 ◽  
Vol 57 (1) ◽  
pp. 194-203 ◽  
Author(s):  
Karel Šindelář ◽  
Vojtěch Kmoníček ◽  
Marta Hrubantová ◽  
Zdeněk Polívka
Keyword(s):  
Serotonin Receptors ◽  
Hydrobromic Acid ◽  
Antidepressant Activity ◽  
Benzoic Acids ◽  
Lithium Aluminium Hydride ◽  
Acid Chlorides ◽  
Activity Inhibition ◽  
Lithium Aluminium ◽  
The Brain

(Arylthio)benzoic acids IIa - IIe and VIb - VId were transformed via the acid chlorides to the N,N-dimethylamides which were reduced either with diborane "in situ" or with lithium aluminium hydride to N,N-dimethyl-(arylthio)benzylamines Ia - Ie and Vb - Vd. Leuckart reaction of the aldehydes IX and X with dimethylformamide and formic acid afforded directly the amines Va and Ve. Demethylation of the methoxy compounds Ia and Ve with hydrobromic acid resulted in the phenolic amines If and Vf. The most interesting N,N-dimethyl-4-(phenylthio)benzylamine (Va) hydrochloride showed affinity to cholinergic and 5-HT2 serotonin receptors in the rat brain and some properties considered indicative of antidepressant activity (inhibition of serotonin re-uptake in the brain and potentiation of yohimbine toxicity in mice).

scholarly journals Peptides Derived from Growth Factors to Treat Alzheimer’s Disease

2021 ◽  
Vol 22 (11) ◽  
pp. 6071
Author(s):  
Suzanne Gascon ◽  
Jessica Jann ◽  
Chloé Langlois-Blais ◽  
Mélanie Plourde ◽  
Christine Lavoie ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Growth Factors ◽  
Signaling Pathways ◽  
Brain Structures ◽  
Therapeutic Strategies ◽  
Native Proteins ◽  
Receptor Sites ◽  
The Brain

Alzheimer’s disease (AD) is a devastating neurodegenerative disease characterized by progressive neuron losses in memory-related brain structures. The classical features of AD are a dysregulation of the cholinergic system, the accumulation of amyloid plaques, and neurofibrillary tangles. Unfortunately, current treatments are unable to cure or even delay the progression of the disease. Therefore, new therapeutic strategies have emerged, such as the exogenous administration of neurotrophic factors (e.g., NGF and BDNF) that are deficient or dysregulated in AD. However, their low capacity to cross the blood–brain barrier and their exorbitant cost currently limit their use. To overcome these limitations, short peptides mimicking the binding receptor sites of these growth factors have been developed. Such peptides can target selective signaling pathways involved in neuron survival, differentiation, and/or maintenance. This review focuses on growth factors and their derived peptides as potential treatment for AD. It describes (1) the physiological functions of growth factors in the brain, their neuronal signaling pathways, and alteration in AD; (2) the strategies to develop peptides derived from growth factor and their capacity to mimic the role of native proteins; and (3) new advancements and potential in using these molecules as therapeutic treatments for AD, as well as their limitations.

scholarly journals The Brain Resting-State Functional Connectivity Underlying Violence Proneness: Is It a Reliable Marker for Neurocriminology? A Systematic Review

2019 ◽  
Vol 9 (1) ◽  
pp. 11 ◽  
Author(s):  
Ángel Romero-Martínez ◽  
Macarena González ◽  
Marisol Lila ◽  
Enrique Gracia ◽  
Luis Martí-Bonmatí ◽  
...  
Keyword(s):  
Functional Connectivity ◽  
Effective Treatment ◽  
Resting State ◽  
Brain Structures ◽  
Prevention Programs ◽  
Angular Gyrus ◽  
Resting State Functional Connectivity ◽  
Treatment And Prevention ◽  
Reliable Marker ◽  
The Brain

Introduction: There is growing scientific interest in understanding the biological mechanisms affecting and/or underlying violent behaviors in order to develop effective treatment and prevention programs. In recent years, neuroscientific research has tried to demonstrate whether the intrinsic activity within the brain at rest in the absence of any external stimulation (resting-state functional connectivity; RSFC) could be employed as a reliable marker for several cognitive abilities and personality traits that are important in behavior regulation, particularly, proneness to violence. Aims: This review aims to highlight the association between the RSFC among specific brain structures and the predisposition to experiencing anger and/or responding to stressful and distressing situations with anger in several populations. Methods: The scientific literature was reviewed following the PRISMA quality criteria for reviews, using the following digital databases: PubMed, PsycINFO, Psicodoc, and Dialnet. Results: The identification of 181 abstracts and retrieval of 34 full texts led to the inclusion of 17 papers. The results described in our study offer a better understanding of the brain networks that might explain the tendency to experience anger. The majority of the studies highlighted that diminished RSFC between the prefrontal cortex and the amygdala might make people prone to reactive violence, but that it is also necessary to contemplate additional cortical (i.e. insula, gyrus [angular, supramarginal, temporal, fusiform, superior, and middle frontal], anterior and posterior cingulated cortex) and subcortical brain structures (i.e. hippocampus, cerebellum, ventral striatum, and nucleus centralis superior) in order to explain a phenomenon as complex as violence. Moreover, we also described the neural pathways that might underlie proactive violence and feelings of revenge, highlighting the RSFC between the OFC, ventral striatal, angular gyrus, mid-occipital cortex, and cerebellum. Conclusions. The results from this synthesis and critical analysis of RSFC findings in several populations offer guidelines for future research and for developing a more accurate model of proneness to violence, in order to create effective treatment and prevention programs.

scholarly journals Glia Not Neurons: Uncovering Brain Dysmaturation in a Rat Model of Alzheimer’s Disease

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 823
Author(s):  
Ekaterina A. Rudnitskaya ◽  
Tatiana A. Kozlova ◽  
Alena O. Burnyasheva ◽  
Natalia A. Stefanova ◽  
Nataliya G. Kolosova
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Prefrontal Cortex ◽  
Brain Structures ◽  
Time Frame ◽  
Oxys Rats ◽  
Unknown Etiology ◽  
Suitable Model ◽  
Model Of Alzheimer’S Disease ◽  
The Brain

Sporadic Alzheimer’s disease (AD) is a severe disorder of unknown etiology with no definite time frame of onset. Recent studies suggest that middle age is a critical period for the relevant pathological processes of AD. Nonetheless, sufficient data have accumulated supporting the hypothesis of “neurodevelopmental origin of neurodegenerative disorders”: prerequisites for neurodegeneration may occur during early brain development. Therefore, we investigated the development of the most AD-affected brain structures (hippocampus and prefrontal cortex) using an immunohistochemical approach in senescence-accelerated OXYS rats, which are considered a suitable model of the most common—sporadic—type of AD. We noticed an additional peak of neurogenesis, which coincides in time with the peak of apoptosis in the hippocampus of OXYS rats on postnatal day three. Besides, we showed signs of delayed migration of neurons to the prefrontal cortex as well as disturbances in astrocytic and microglial support of the hippocampus and prefrontal cortex during the first postnatal week. Altogether, our results point to dysmaturation during early development of the brain—especially insufficient glial support—as a possible “first hit” leading to neurodegenerative processes and AD pathology manifestation later in life.

scholarly journals Consciousness, decision making, and volition: freedom beyond chance and necessity

2021 ◽  
Author(s):  
Hans Liljenström
Keyword(s):  
Decision Making ◽  
Free Will ◽  
Brain Activity ◽  
Brain Structures ◽  
Complex Process ◽  
Neural Information ◽  
Neural Information Processing ◽  
Stochastic Population Model ◽  
The Brain

AbstractWhat is the role of consciousness in volition and decision-making? Are our actions fully determined by brain activity preceding our decisions to act, or can consciousness instead affect the brain activity leading to action? This has been much debated in philosophy, but also in science since the famous experiments by Libet in the 1980s, where the current most common interpretation is that conscious free will is an illusion. It seems that the brain knows, up to several seconds in advance what “you” decide to do. These studies have, however, been criticized, and alternative interpretations of the experiments can be given, some of which are discussed in this paper. In an attempt to elucidate the processes involved in decision-making (DM), as an essential part of volition, we have developed a computational model of relevant brain structures and their neurodynamics. While DM is a complex process, we have particularly focused on the amygdala and orbitofrontal cortex (OFC) for its emotional, and the lateral prefrontal cortex (LPFC) for its cognitive aspects. In this paper, we present a stochastic population model representing the neural information processing of DM. Simulation results seem to confirm the notion that if decisions have to be made fast, emotional processes and aspects dominate, while rational processes are more time consuming and may result in a delayed decision. Finally, some limitations of current science and computational modeling will be discussed, hinting at a future development of science, where consciousness and free will may add to chance and necessity as explanation for what happens in the world.

Synthesis of 1-acyl- and 1-(thioacyl)-4-benzylpiperazines as potential antidepressants

1990 ◽  
Vol 55 (7) ◽  
pp. 1817-1827 ◽  
Author(s):  
Vojtěch Kmoníček ◽  
Emil Svátek ◽  
Jiří Holubek ◽  
Miroslav Ryska ◽  
Martin Valchář ◽  
...  
Keyword(s):  
Benzoic Acid ◽  
Thionyl Chloride ◽  
Antidepressant Activity ◽  
Acid Chlorides ◽  
Phosphorus Pentasulfide ◽  
Antidepressant Agent ◽  
Dimethylaminobenzoic Acid ◽  
Amino Amides

2-Nitro, 3-nitro- and 4-nitrobenzoyl chloride were reacted with 1-benzylpiperazine in benzene in the presence of triethylamine and gave the amides IV-VI, the first of which is considered a bioisostere of the antidepressant agent piberaline (I). 2-Dimethylamino-, 3-dimethylamino- and 4-dimethylaminobenzoic acid were treated with thionyl chloride in benzene in the presence of triethylamine or pyridine, and the acid chlorides formed were reacted in situ with 1-benzylpiperazine affording the amides VII-IX. The amides I and IV-VI were transformed by treatment with phosphorus pentasulfide in pyridine to the thioamides X-XIII. 4-(Dimethylaminomethyl)benzoic acid was reacted with 1-benzylpiperazine in dimethylformamide in the presence of N,N'-carbonyldiimidazole and afforded the amide XIV. Heating of ethyl 5-methylimidazole-4-carboxylate with 1-benzylpiperazine to 200-210 °C gave the amide XV together with the unexpected 1-benzyl-4-ethylpiperazine (XVI). The oily or crystalline bases of the amino amides or thioamides were mostly transformed to crystalline salts and characterized by spectra. Out of the compounds prepared only X (V⁄FB-17 070) and XIV (V⁄FB-17 114) showed indications of efficacy in tests which are considered indicative of antidepressant activity. Compounds VII, VIII, and X appeared to be mildly antidopaminergic - similarly like piberaline (I), and compounds IV, V, XI, XIV, and XV on the contrary showed signs of dopaminominetic activity.

Sign in / Sign up

Export Citation Format

Share Document