4,4'-Bismoschamine: biomimetic synthesis and evidence to support structural equivalency to montamine.

The dimeric natural product montamine was originally reported as two N-feruloylserotonin (moschamine) units linked by a nitrogen-nitrogen bond, but our recent synthesis of this symmetrical diacyl hydrazide structure revealed this to be incorrect. We subsequently hypothesized that the moschamine subunits were linked through the indole C4 site and that montamine was structurally identical to 4,4'-bismoschamine, a known natural product present in safflower oil. However, given that authentic samples of both montamine and 4,4'-bismoschamine were unavailable and that the NMR data for the natural products were recorded in different solvents, we were unable to unequivocally prove this hypothesis. A recent publication that claims montamine and 4,4'-bismoschamine are not the same natural product prompts us to disclose our own findings on this matter. A biomimetic synthesis of 4,4'-bismoschamine was developed that hinged on oxidative coupling of N-Boc-serotonin followed by elaboration of the resulting 4,4'-dimer to the natural product. A detailed comparison of the NMR data for synthetic 4,4'-bismoschamine with that reported for montamine revealed that while the 1H NMR data were in good agreement, the 13C NMR data displayed some discrepancies. In light of this result, the NMR data for several literature compounds was analyzed, the results of which revealed that the upfield chemical shifts of the methylene protons in the 1H NMR of montamine is unique to 4,4'-bistryptamines, supporting our initial statement that montamine and 4,4'-bismoschamine are structurally equivalent. Given that the main differences in the 13C NMR data between montamine and synthetic 4,4'-bismoschamine occur at the quaternary carbons, we propose that these peaks have been misassigned from a 13C NMR spectrum that was obtained from an impure sample and/or the small amount of montamine (4 mg) isolated from the natural source.

Synthesis of Pyrrolo[2,3-d]pyrimidines by Copper-Mediated Carbomagnesiations of N-Sulfonyl Ynamides and Application to the Preparation of Rigidin†A and a 7-Azaserotonin Derivative.

The treatment of readily available N-alkynyl-5-iodo-6-sulfamido-pyrimidines with iPrMgCl⋅LiCl followed by a transmetalation with CuCN⋅2 LiCl produces, after intramolecular carbocupration, metalated pyrrolo[2,3-d]pyrimidines. Quenching of these pyrimidines with allylic halides or acid chlorides results in polyfunctional pyrrolo[2,3-d]pyrimidines. Further reaction with ICl and a Negishi cross-coupling, using PEPPSI-iPr as the catalyst, furnishes fully substituted N-heterocycles. A formal synthesis of the marine alkaloid rigidin A has been achieved as well as the preparation of a derivative of 7-azaserotonine, related to the natural hormone serotonin.

Alkaloids from the Traditional Chinese Medicine ChanSu: synthesis-enabled structural reassignment of bufopyramide to bufoserotonin C.

A synthesis of putative bufopyramide has shown the structure assigned to the natural product to be incorrect. The spectroscopic data for the natural product bufopyramide matches that obtained from a synthetic sample of bufoserotonin C, confirming that the two natural products are not distinct, but instead the same compound.

Uso de antipsicóticos fuera de indicación en los mayores / No disponible

El uso de fármacos antipsicóticos es frecuente en los trastornos psicogeriátricos. Los antipsicóticos son los fármacos que han demostrado mayor eficacia en el tratamiento de la esquizofrenia y otros trastornos psicóticos del anciano. Sin embargo en otras indicaciones como los síntomas neuropsiquiátricos de la demencia su eficacia es más modesta y los efectos adversos pueden ser graves, incluyendo un aumento de accidentes cerebrovasculares, efectos metabólicos, síntomas extrapiramidales, caídas, empeoramiento cognitivo, arritmias, neumonías y aumento de la mortalidad. En 2004 la FDA (Food and Drugs Administration) advirtió la posible asociación del tratamiento con risperidona y olanzapina y el aumento de accidentes cerebrovasculares. Otras revisiones posteriores demostraron que el riesgo era similar para los antipsicóticos convencionales o clásicos, surgiendo una alerta similar para éstos en 2008. En España la prescripción de antipsicóticos atípicos en personas mayores de 75 años requiere un documento específico o "visado" y muchos de estos antipsicóticos se utilizan fuera de indicación, por ejemplo en los pacientes con demencia. Solamente la risperidona está indicada por la FDA y por la Agencia Española para el uso de Medicamentos y Productos Sanitarios (AEMPS) para el tratamiento de los trastorno de conducta en los pacientes con demencia. Sin embargo otros antipsicóticos atípicos han demostrado eficacia, aunque moderada, para el tratamiento de la agitación o la psicosis en los pacientes con demencia. Estos usos se enmarcan "fuera de indicación", requieren un protocolo específico y puede ser causa de preocupación para los prescriptores, pacientes, cuidadores y autoridades sanitarias

Use of antipsychotics drugs in the elderly is frequent in psychogeriatric disorders. For exemple antipsychotics are the most effective drugs used in therapy of schizophrenia and other psychotics disorders in elderly. However in other indications such as neuropsychiatric symptoms in dementia efficacy are less strong and adverse effects can include an increase of mortality risk, cerebrovascular events, metabolic effects, extrapiramidal symptoms, falls, as well as cognitive worsening, cardiac arrhythmia an pneumonia. In 2004 FDA warned of an association between risperidone and olanzapine with cerebrovascular events. Additional clinical trials of others atypical and conventional antipsychotics show similar risk with mortality and FDA warning now applies to all antipsychotics in 2008. In Spain prescription of atypical antipsychotics in older of 75 years old requires a specifically document and most antipsychotics are employed in off-label prescription as in dementia patients. Only risperidone is approved by FDA and Spanish Drugs Agency to use in dementia suffers. However others atypical antipsychotics as olanzapine, quetiapine and aripiprazol can be effective on agitation or psychosis in dementia. So these uses are off-label and can be cause for concern

Unusual reactivity of ß-hydroxy-serotonin, a forgotten serotonin derivative.

Serotonin (5-HT) is a well-known biogenic amine which regulates mood, sleep, and is involved in muscle contraction and blood coagulation. Based on an analogy to norepinephrine, a ß-hydroxylated derivative of dopamine which has diverse physiological functions, beta-hydroxy-serotonin (ß-OH-5-HT) originally encouraged interest as a potential pharmacological agent. Four decades ago, its organic synthesis was attempted. However, due to difficulties with the synthesis and the compound's instability, rigorous identification and characterization of ß-OH-5-HT proved evasive. Here, we successfully synthesized ß-OH-5-HT from 5-HT using a Pseudomonas enzyme, tryptophan side chain oxidase type I (TSOI), and we determined the structure by 2D-NMR and characterized ß-OH-5-HT in detail. The CD spectra showed no optical activity, suggesting a racemic mixture. To separate DL-ß-OH-5-HT, we synthesized L-Ala-5-HT and derivatized it into erythro- and threo-L-Ala-ß-OH-5-HT with TSOI. Interestingly, both isolated fractions returned to a diastereoisomeric mixture within two hours at pH 5.0. Later, we found that, under acidic conditions, ß-OH-5-HT readily reacted with nucleophiles like alcohols or thiols, yielding a variety of DL-ß-substituted-5-HT. The unusual properties of ß-OH-5-HT might be attributed to the unique nature of a ß-hydroxyl group adjacent to an indole ring and amino group. The mechanism for the rapid racemization of ß-OH-5-HT is discussed.

Synthesis, physicochemical characterization and membrane interactions of a homologous series of N-acylserotonins: Bioactive, endogenous conjugates of serotonin with fatty acids.

N-Acylserotonins (NASTs), present in the mammalian gastro-intestinal tract and central nervous tissues, exhibit significant biological and pharmacological activities. In the present study, a homologous series of NASTs have been synthesized and characterized. Differential scanning calorimetric studies show that in the dry and hydrated states the transition temperatures, enthalpies, and entropies of NASTs exhibit odd-even alternation. Both odd and even chain length NASTs independently display linear dependence of the transition enthalpies and entropies on the chain length under dry as well as hydrated conditions, suggesting that the molecular packing and intermolecular interactions in each series (odd or even) are likely to be similar for NASTs with different acyl chain lengths in the dry state as well as in the hydrated state. Powder X-ray diffraction studies indicated that the incremental increase in the d-spacing per CH2group is 1.023 Å, suggesting that the lipid acyl chains are most likely packed in an interdigitated fashion. Results of computational studies are consistent with this and suggest that the acyl chains of the NASTs are tilted with respect to the bilayer normal. Incorporation of N-myristoylserotonin (NMST) into dimyristoylphosphatidylcholine (DMPC) membranes did not significantly affect the phase transition properties at low mole fractions (1-5 mol%), although distinct decrease in the chain-melting transition temperature and increase in the pretransition temperature were observed at higher contents (7.5-30 mol%), suggesting that NMST increases the stability of the tilted gel phase (L(ß)') but destabilizes the ripple phase (P(ß)'). These observations provide a thermodynamic basis for understanding the functional role of NASTs in their parent tissues.

Near native binding of a fluorescent serotonin conjugate to serotonin type 3 receptors.

Described is the synthesis of 5-hydroxytryptamine-tetramethylrhodamine (5HT*); an indole nitrogen linked fluorescent conjugate of serotonin. Through a series fluorescence quenching experiments and experiments in the presence of a known competitive antagonist (Granisetron), it was shown that 5HT* specifically binds to purified homo-pentameric type-3 human serotonin receptors (5HT(3A)). The measured dissociation constant and Hill coefficient are K(d) = 83 ± 3 nM and n = 3.1 ± 0.3, respectively which is indicative of multi-ligand binding and cooperativity similar to that of unconjugated serotonin.

In vivo examination of 111In-bis-5HT-DTPA to target myeloperoxidase in atherosclerotic ApoE knockout mice.

PURPOSE: The aim of the study is to assess the feasibility of imaging specific activity of myeloperoxidase (MPO), a leukocyte-derived enzyme with important role in atherosclerosis, by SPECT/CT using a novel radiotracer, (111)In-bis-5-hydroxytryptamide-diethylenetriamine-pentaacetate ((111)In-bis-5HT-DTPA). METHODS: Bis-5HT-DTPA was synthesized. Oligomerization of bis-5HT-DTPA in the presence of MPO/H(2)O(2) was studied and confirmed using MALDI-TOF. Apolipoprotein E knockout (ApoE KO) mice was used as an atherosclerosis-prone rodent model. Biodistribution assay and micro SPECT/CT imaging were carried out to prove the atherosclerosis targeting of (111)In-bis-5HT-DTPA in the ApoE KO mice. RESULTS: MALDI-TOF spectrum showed that the 5HT base agent can self oligomerize after activating by MPO. From the biodistribution study, (111)In-bis-5HT-DTPA was quantified to be retained markedly higher while eliminated much slower in the aortas of the ApoE KO mice than that of the wild type (WT) mice within 1 h post-injection. The nuclear imaging showed significantly higher uptake in the aorta of the ApoE KO mice than that of the WT mice at least within 2 h post-injection. CONCLUSION: This study described the pharmacokinetics and biodistribution of (111)In-bis-5HT-DTPA in ApoE KO mice and validated its utilization for early detection of atherosclerotic marker, MPO, in the aortic wall of atherosclerosis-prone rodent model.

N-Caffeoyl serotonin as selective COX-2 inhibitor.

The inhibitory effects of the synthetic serotonin analogues (1-8) on COX (1 and 2) were evaluated. Two serotonin derivatives (4 and 8) showed inhibitory effect of COX (1 and 2). Especially, 4 exhibited excellent inhibitions on COX-2 with extremely high potency (IC(50)=42.5 µM). The inhibitory activities of cinnamic acid derivatives and serotonin were evaluated to clarify whether inhibitory activities of compound 4 and 8 are due to cinnamic acid moiety or serotonin moiety. Caffeic acid and N-caffeoyl serotonin (4) exhibited selective inhibition of COX-2 compared to aspirin. Comparison caffeic acid with 4 suggested that the linkage of caffeic acid and serotonin enhance COX-2 inhibition. Comparison of structures of caffeic acid and sinapic acid implied that catechol moiety of cinnamic acid derivatives is a major contributing factor for selective inhibition of COX-2. The selective COX-2 inhibitory activity of compound 4 is significant and could be employed as drugs against inflammatory and allergy.

Synthesis of dopamine and serotonin derivatives for immobilization on a solid support.

The two important neurotransmitters dopamine and serotonin are synthesized with short PEG tethers and immobilized on a magnetic solid support. The tether is attached to the aromatic moiety of the neurotransmitters to conserve their original functional groups. This approach causes minimal alteration of the original structure with the aim of optimizing the immobilized neurotransmitters for aptamer selection by SELEX. For the dopamine derivative, the tether is attached to the aromatic core of a dopamine precursor by the Sonogashira reaction. For serotonin, a link to the indole core is introduced by a Claisen rearrangement from the allylated phenol moiety of serotonin. The tethers are azide-functionalized, which enables coupling to alkyne-modified magnetic beads. The coupling to the magnetic beads is quantified by UV spectroscopy using Fmoc-monitoring of the immobilized dopamine and serotonin derivatives.

Serotonin derivatives as inhibitors of beta-secretase (BACE 1).

All serotonin derivatives described here (1-9) inhibited BACE 1 in a dose dependent manner. The 50% Inhibition Concentration (IC50) of N-cinnamoyl serotonin (1) was 86.7 +/- 4.0 microM. The peptide conjugation of serotonin derivatives influenced the BACE 1 inhibitory activity. Among serotonin derivatives (1-8), introduction of substituents, such as hydroxyl and methoxy groups at the 4'-position decreased the inhibitory activity (N-p-coumaroyl serotonin (2), N-p-methoxy cinnamoyl serotonin (3)). With a hydroxylgroup at the 4'-position, and the meta-hydroxy function being substituted by a hydroxyl group or methoxy group (N-caffeoyl serotonin (4), N-feruloyl serotonin (5)), inhibitory activity was weakened, (IC50 >400 microM). BACE 1 inhibitory activity was effected by the substituents of the cinnamic acid moiety. This is the first report on Structure-Activity-Relationships (SAR) for the BACE 1-inhibiting activity of serotonin derivatives. These serotonin derivatives, which have anti-oxidative effects as well are expected to be useful in the study of the mechanisms of Alzheimer's disease.

Synthesis and structure-activity relationships of phenylpropanoid amides of serotonin on tyrosinase inhibition.

In this manuscript, we synthesized a series of phenylpropanoid amide of serotonin 1-9, analyzed their structural importance for two biologic activities (antioxidant activity and tyrosinase inhibitory activity). While the serotonin moiety and the amide linkage of serotonin derivatives affect antioxidant activity strongly, the serotonin moiety, the amide linkage and the cinnamic acid moiety affect tyrosinase inhibitory activity. Among tested compounds, compound 4 which contains cathechol moiety exhibited the most antioxidant activity (EC(50) = 19.4 ± 2.0 µM), and compound 6 exhibited significant tyrosinase inhibitory activity (IC(50) = 5.4 ± 3.6 µM). Our data suggests that a useful clue for the design and development of new tyrosinase inhibitors.

Discovery of N-methyl-1-(1-phenylcyclohexyl)methanamine, a novel triple serotonin, norepinephrine, and dopamine reuptake inhibitor.

The current work discloses a novel cyclohexylarylamine chemotype with potent inhibition of the serotonin, norepinephrine, and dopamine transporters and potential for treatment of major depressive disorder. Optimized compounds 1 (SERT, NET, DAT, IC(50)=169, 85, 21 nM) and 42 (SERT, NET, DAT IC(50)=34, 295, 90 nM) were highly brain penetrant, active in vivo in the mouse tail suspension test at 30 mpk po and were not general motor stimulants.

Discovery of N-methyl-1-(1-phenylcyclohexyl)ethanamine, a novel triple serotonin, norepinephrine and dopamine reuptake inhibitor.

Novel chiral cyclohexylaryl amines were developed with potent reuptake inhibition against the serotonin, norepinephrine and dopamine transporters and activity at 10 and 30 mpk PO in the mouse tail suspension test. Prototype compound 31 (SERT, NET, DAT IC(50) ≤ 1, 21, 28 nM) was highly brain penetrant, had minimal CYP and hERG inhibition, and represents a previously undisclosed architecture with potential for treatment of major depressive disorder.

N-[(Dihydroxyphenyl)acyl]serotonins as potent inhibitors of tyrosinase from mouse and human melanoma cells.

A series of N-acyl derivatives of tyramine, tryptamine, and serotonin were synthesized and tested on anti-melanogenic activity. The serotonin derivatives such as N-caffeoylserotonin (3) and N-protocatechuoylserotonin (9) were inhibitory to tyrosinase from mouse B16 and human HMV-II melanoma cells, while the corresponding derivatives of tryptamine and 5-methoxytryptamine were almost inactive or less active than the serotonin derivatives. The inhibitory activity of the serotonin derivatives increased with increasing number of phenolic hydroxyl groups in the acyl moiety. Melanin formation in the culture of B16 cells was suppressed by 3 and 9 with no cytotoxicity in the concentration range tested (IC(50)=15, 3 and 111muM for 3, 9, and kojic acid, respectively). Thus the N-acylserotonin derivatives having a dihydroxyphenyl group are potential anti-melanogenic agents. Their inhibition of tyrosinase is primarily performed through the 5-hydroxyindole moiety and further strengthened by the phenolic hydroxyl groups in the acyl moiety.

New N-arachidonoylserotonin analogues with potential "dual" mechanism of action against pain.

N-arachidonoylserotonin (AA-5-HT, 1a) is an inhibitor of fatty acid amide hydrolase (FAAH) that acts also as an antagonist of transient receptor potential vanilloid-type 1 (TRPV1) channels and is analgesic in rodents. We modified the chemical structure of 1a with the aim of developing "hybrid" FAAH/TRPV1 blockers more potent than the parent compound or obtaining analogues with single activity at either of the two targets to study the mechanism of the analgesic action of 1a. Thirty-eight AA-5-HT analogues, containing a serotonin "head" bound to a variety of lipophilic moieties via amide, urea, or carbamate functionalities, were synthesized. Unlike 1a, most of the new compounds possessed activity at only one of the two considered targets. The amides 1b and 1c of alpha- and gamma-linolenic acid, however, showed "hybrid" activity similar to 1a. The carbamate 3f (OMDM106), although unable to antagonize TRPV1 receptors, was the most potent FAAH inhibitor in this study (IC50=0.5 microM). Compounds 3f and 1m (OMDM129), which exhibited activity at only FAAH or TRPV1, respectively, were 10-fold less potent than 1a at preventing formalin-induced hyperalgesia in mice.

Serotonin 5-HT1A receptor activation prevents phosphorylation of NMDA receptor NR1 subunit in cerebral ischemia

The mechanisms involved in the neuroprotective effect of serotonin 5-HT1Areceptor agonists on brain damage induced by ischemia remain to be fully elucidated.Given that serotonergic drugs may regulate N-methyl-D-aspartate (NMDA)receptor function, which is implicated in events leading to ischemia-induced neuronalcell death, this study sought to determine the effects of the selective 5-HT1Areceptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), on thelevels of NMDA receptor NR1 subunit in gerbil hippocampus after transient globalcerebral ischemia. Pretreatment with 8-OH-DPAT (1 mg/kg) prevented the neuronalloss in CA1 subfield 72 h after ischemia. NMDA receptor NR1 levels in wholehippocampus were not affected 24 h after ischemia, but the levels of the subunitphosphorylated at the protein kinase A (PKA) site, pNR1(Ser897), were significantlyincreased, and this increase was prevented by the same 8-OH-DPAT dose, a probableconsequence of the increased phosphatase 1 (PP1) enzyme activity found inischemic gerbils pretreated with the 5-HT1A receptor agonist. The results suggestthat NR1 subunit phosphorylation plays a role in the neuroprotective effect of 8-OH-DPAT on cell damage induced by global cerebral ischemia in the gerbil hippocampusand support the potential interest of 5-HT1A receptor activation in the search for neuroprotective strategies (AU)

No disponible

1-Oxo-5-hydroxytryptamine: a surprisingly potent agonist of the 5-HT3 (serotonin) receptor.

A novel synthetic route to 1-oxo-5-hydroxytryptamine, the benzofuran analogue of serotonin, has been developed. The new synthesis proceeds via the [3+2] cycloaddition of p-benzoquinone and 2,3-dihydrofuran, followed by a Lewis acid-catalyzed isomerization. This molecule proves to be a competent agonist (equipotent to serotonin) of the 5-HT3 receptor, demonstrating that the indolic proton of serotonin is not essential to its activation of the receptor.

Synthesis of 7-azaserotonin: its photophysical properties associated with excited state proton transfer reaction.

We report the synthesis of 3-(2-aminoethyl)-5-ol-1H-pyrrolo[2,3-b]pyridine (7-azaserotonin), which may potentially serve as an agonist or antagonist of serotonin receptors. In alcohols, the solvent (e.g., ethanol) catalyzed proton-transfer reaction takes place for 7-azaserotonin in the excited state, resulting in dual emission. Conversely, excited-state deprotonation takes place in neutral aqueous solution. The unique excitation behavior makes 7-azaserotonin versatile as a potential bioprobe.

[Fluorescent-labeled lipophilic analogues of serotonin, dopamine, and acetylcholine: synthesis, mass spectrometry, and biological activity]. / Fluorestsentnomechenye lipofil'nye analogi serotonina, dofamina i atsetilkholina: sintez, mass-spektrometriia i biologicheskaia aktivnost'.

4,4-Difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-dodecanoyl derivatives of serotonin, dopamine, choline, and N,N-dimethylaminoethanol, with the fluorescence maximum at 512 nm (lambda(exc) 470 nm), and 4,4-difluoro-5,7-diphenyl-4-bora-3a,4a-diaza-s-indacene-3-dodecanoyl derivatives of choline and N,N-dimethylaminoethanol, with the fluorescence maximum at 554 nm (lambda(exc) 470 nm), were synthesized. These compounds yield protonated molecular ions of 100% intensity upon mass spectrometry with electrospray ionization at atmospheric pressure. The fragmentation of molecular ions under the conditions of secondary mass spectrometry mainly proceeds through the elimination of hydrogen fluoride from the fluorescent core of the molecules. Experiments on sea urchin Lytechinus variegatus embryos and larvae showed that these compounds easily penetrate into the cells and are accumulated in the cytoplasm. They do not differ in their biological activity from similar derivatives of arachidonic acid described previously and are agonists of serotonin or acetylcholine or antagonists of nicotinic acetylcholine receptors. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 5; see also http: // www.maik.ru.