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.

Potential antidepressants: 2-(fluoro-, chloro-, bromo- and cyanophenylthio)benzylamines as inhibitors of 5-hydroxytryptamine and noradrenaline re-uptake in brain

1991 ◽  
Vol 56 (11) ◽  
pp. 2468-2481 ◽  
Author(s):  
Vojtěch Kmoníček ◽  
Josef Pomykáček ◽  
Jiří Holoubek ◽  
Emil Svátek ◽  
Martin Valchář ◽  
...  
Keyword(s):  
Amino Acid ◽  
Brain Structures ◽  
Lithium Aluminium Hydride ◽  
Selective Inhibitors ◽  
Hexamethylphosphoric Triamide ◽  
Lithium Aluminium ◽  
Cuprous Cyanide ◽  
Benzoyl Chlorides ◽  
Pharmacological Testing

2-, 3- and 4-Fluorothiophenol, 2-, 3- and 4-chlorothiophenol, and 2-bromothiophenol were converted in two steps into the corresponding 2-(halogenphenylthio)benzoyl chlorides IV which afforded amides V and VI by reaction with dimethylamine and N,N,N’-trimethylethylenediamine. The amides were reduced either by lithium aluminium hydride or by diborane to benzylamines Ia-Ig and IIa-IIc. The reaction of 2-chlorobenzaldehyde with 3-bromothiophenol or 4-bromothiophenol afforded aldehydes VIIh and VIIi yielding subsequently benzylamines Ih and Ii by subsequent reducing amination. Cyano analogs Ij and Il were obtained from the bromo derivatives Ig and Ii by their reaction with cuprous cyanide in hexamethylphosphoric triamide. The synthesis of compound Ik was effected via aldehyde acid VIIm affording amino acid Im on reducing amination. The conversion of the latter to amide In and its dehydration yielded nitrile Ik. Some of the compounds synthesized, especially Ic, Id, Ie and If, are efficient and selective inhibitors of re-uptake of 5-hydroxytryptamine in brain structures. The most interesting from this aspect is compound If(hydrochloride VUFB-17649) of this series which was chosen for detailed pharmacological testing.

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).

Potential antidepressants: 1-(2-(Methoxy- and hydroxyphenylthio)phenyl)-2-propylamines

1990 ◽  
Vol 55 (4) ◽  
pp. 1077-1098 ◽  
Author(s):  
Jiří Urban ◽  
Zdeněk Šedivý ◽  
Jiří Holubek ◽  
Emil Svátek ◽  
Miroslav Ryska ◽  
...  
Keyword(s):  
Ethyl Formate ◽  
Secondary Amines ◽  
Primary Amines ◽  
Alternative Route ◽  
Lithium Aluminium Hydride ◽  
Tertiary Amines ◽  
Lithium Aluminium ◽  
Boron Tribromide ◽  
Pharmacological Testing ◽  
By Products

2-(Methoxyphenylthio)benzaldehydes Xa-Xd were reacted with nitroethane in boiling acetic acid to give the corresponding 1-aryl-2-nitropropenes XIIa-XIId; benzonitriles XIIIa and XIIIc and benzaldoximes XXIc and XXId were isolated as by-products. Chromatographed compounds XIIa-XIId were reduced with lithium aluminium hydride to the primary amines VIIa-VIId, and formylated by heating with ethyl formate to the formamides XIVa, XIVc, and XIVd. Reduction of the formamides with lithium aluminium hydride afforded the secondary amines VIIIa, VIIIc, and VIIId, and methylation of the primary amines with formic acid and formaldehyde gave the tertiary amines IXa, IXc, and IXd. Compound VIIIa was prepared also by an alternative route starting from the nitrile XIIIa and proceeding via XIXa and XIVa. Some of the methoxylated amines were demethylated either by heating with pyridine hydrochloride or by treatment with boron tribromide to the title compounds IVa, IVc, Vc, Vd, VIa, and VIc. The amines prepared were transformed to salts for characterization and for pharmacological testing. Compound VIIIa (hydrogen oxalate V⁄FB-15 475) showed clearly the character of a potential antidepressant.

The Brain from Inside Out

2019 ◽  
Author(s):  
György Buzsáki
Keyword(s):  
Brain Research ◽  
Brain Structures ◽  
Fundamental Function ◽  
Sensory Inputs ◽  
Highly Active ◽  
Self Organized ◽  
The World ◽  
Cognitive Faculties ◽  
The Brain ◽  
Inside Out

The Brain from Inside Out takes a critical look at contemporary brain research and reminds us that theoretical framework does matter. Current technology-driven neuroscience is still largely fueled by an empiricist philosophy assuming that the brain’s goal is to perceive, represent the world, and learn the truth. An inevitable consequence of this framework is the assumption of a decision-making homunculus wedged between our perception and actions. In contrast, The Brain from Inside Out advocates that the brain’s fundamental function is to induce actions and predict the consequences of those actions to support the survival and prosperity of the brain’s host. Brains constantly test their hypotheses by producing actions rather than searching for the veridical objective world. Only actions can provide a second opinion about the relevance of the sensory inputs and provide meaning for and interpretation of those inputs. In this inside-out framework, it is not sensations that teach the brain and build up its circuits. Instead, the brain comes with a preconfigured and self-organized dynamics that constrains how it acts and views the world. Both its anatomical and physiological organizations are characterized by an enormous diversity which spans several orders of magnitude. The two ends of this continuous landscape give rise to apparently distinct qualitative features. A small core of strongly interconnected, highly active neurons provides fast and “good-enough” answers in needy situations by generalizations, whereas detailed and precise solutions rely on the contribution of the more isolated and sluggish majority. In this non-egalitarian organization, preexisting nonsense brain patterns become meaningful through action-based experience. The inside-out framework offers an alternative strategy to investigate how brain operations give rise to our cognitive faculties, as opposed to the outside-in approach that explores how our preconceived ideas map onto brain structures.

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.

Convenient Synthesis of (Z)-7- and (E)-9-dodecene-1-yl Acetate, Components of Some Lepidoptera Insect Sex Pheromone

2017 ◽  
Vol 68 (1) ◽  
pp. 180-185
Author(s):  
Adriana Maria Andreica ◽  
Lucia Gansca ◽  
Irina Ciotlaus ◽  
Ioan Oprean
Keyword(s):  
Sex Pheromone ◽  
Coupling Reaction ◽  
Coupling Scheme ◽  
Lithium Aluminium Hydride ◽  
Terminal Alkyne ◽  
Mercury Derivative ◽  
Lithium Aluminium ◽  
Convenient Synthesis ◽  
Practical Synthesis ◽  
Insect Sex

Were developed new and practical synthesis of (Z)-7-dodecene-1-yl acetate and (E)-9-dodecene-1-yl acetate. The routes involve, as the key step, the use of the mercury derivative of the terminal-alkyne w-functionalised as intermediate. The synthesis of (Z)-7-dodecene-1-yl acetate was based on a C6+C2=C8 and C8+C4=C12 coupling scheme, starting from 1,6-hexane-diol. The first coupling reaction took place between 1-tert-butoxy-6-bromo-hexane and lithium acetylide-ethylendiamine complex obtaining 1-tert-butoxy-oct-7-yne, which is transformed in di[tert-butoxy-oct-7-yne]mercury. The mercury derivative was directly lithiated and then alkylated with 1-bromobutane obtaining 1-tert-butoxy-dodec-7-yne. After acetylation and reduction with lithium aluminium hydride of 7-dodecyne-1-yl acetate gave (Z)-7-dodecene-1-yl acetate with 96 % purity. The synthesis of (E)-9-dodecene-1-yl acetate was based on a C8+C2=C10 and C10+C2=C12 coupling scheme, starting from 1,8-octane-diol. The first coupling reaction took place between 1-tert-butoxy-8-bromo-octane and lithium acetylide-ethylendiamine complex obtaining 1-tert-butoxy-dec-9-yne, which is transformed in di[tert-butoxy-dec-9-yne]mercury. The mercury derivative was directly lithiated and then alkylated with 1-bromoethane obtaining 1-tert-butoxy-dodec-9-yne. After reduction with lithium aluminium hydride of 1-tert-butoxy-(E)-9-dodecene and acetylation was obtained (E)-9-dodecene-1-yl acetate with 97 % purity.

Neuro-AIDS: Current status and Challenges to Antiretroviral Drug Therapy (ART) for Its Treatment.

2020 ◽  
Vol 15 ◽  
Author(s):  
Smita P. Kakad ◽  
Sanjay J. Kshirsagar
Keyword(s):  
Nervous System ◽  
Antiretroviral Therapy ◽  
Highly Active Antiretroviral Therapy ◽  
Sensory Neuropathy ◽  
Current Status ◽  
Viral Reservoir ◽  
Viral Reservoirs ◽  
Highly Active ◽  
Aids Therapy ◽  
The Brain

Introduction: The infiltration of HIV into the brain alters the functions of the nervous system known as NeuroAIDS. It leads to neuronal defects clinically manifested by motor and cognitive dysfunctions. Materials/Methods: Current antiretroviral therapy can prevent viral replication but cannot cure the disease completely. HAART-Highly active antiretroviral therapy used for the treatment of HIV infection. Challenges in neuro-AIDS therapy are as shown in the graphical abstract. One of the challenges is latent viral reservoirs like the brain; which acts as a sanctuary site for viruses. Nearly ~50% of HIV patients show neuropathological signs. Nervous system related disorders including AIDS dementia, sensory neuropathy, and myelopathy have a 25% of prevalence in patients having access to a highly active combination antiretroviral therapy. Results/Conclusions: Brain is one of the viral sanctuary sites for HIV. The current need of neuro-AIDS therapy is to target the brain as a viral reservoir. Drugs should cross or bypass the blood-brain barrier to reach the brain with effective concentrations. Current research on novel drug delivery approaches may prove helpful to treat neuro-AIDS and related disorders effectively.

3-(s-Hydrindacen-4-yl)propylamines and 4-(s-hydrindacen-4-yl)butylamines; Synthesis and pharmacological screening

1981 ◽  
Vol 46 (8) ◽  
pp. 1800-1807 ◽  
Author(s):  
Zdeněk Vejdělek ◽  
Marie Bartošová ◽  
Miroslav Protiva
Keyword(s):  
Malonic Acid ◽  
Local Anaesthetics ◽  
Lithium Aluminium Hydride ◽  
Spasmolytic Activity ◽  
Lithium Aluminium ◽  
Malonic Acid Derivatives ◽  
Pharmacological Screening ◽  
Hydroxyethyl Piperazine

4-Chloromethyl-s-hydrindacene (VIIa) was transformed via the malonic acid derivatives VIIIa and IXa to the acid Xb which afforded in four steps the homological acid Xc. Reactions of chlorides of both acids (XIbc ) with dimethylamine, 1-methylpiperazine and 1-(2-hydroxyethyl)piperazine led to the amides XIIbc-XIVbc which were reduced with lithium aluminium hydride to the title compounds IVcd-VIcd. The amines obtained show central neuroleptic effects only in subtoxic doses; they are also potent local anaesthetics and have significant spasmolytic activity of the neurotropic as well as musculotropic type.

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