Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Tryptamines”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 829 records · Page 46Linked to original sources
PubMed1979

Effect of nerve activity on the in vivo release of [3H]serotonin continuously formed from L-[3H]tryptophan in the caudate nucleus of the cat.

A new isotopic approach has been developed to study the in vivo release of serotonin (5-HT). 'Encéphale isolé' cats were implanted with a push-pull cannula in the ventrocaudal part of the head of the caudate nucleus to estimate the release of [3H]5-HT continuously synthesized from L-[3H]tryptophan. Both [3H]5-HT and [3H]tryptamine were found in superfusates. Resting steady state in the release of [3H]indoleamines was observed as soon as 20 min after the beginning of the superfusion with L-[3H]tryptophan; the levels of [3H]5-HT in superfusates were 2.5 times those of [3H]tryptamine and about 6 times the blank value. They were markedly enhanced in the presence of fluoxetine (5 x 10(-6)M), a blocker of the 5-HT uptake process. A marked increase in the release of [3H]5-HT was seen during the local depolarization of 5-HT terminals with potassium chloride (60 mM) or batrachotoxin (10(-6)M) or during the stimulation of 5-HT cell bodies in the nucleus raphe dorsalis with L-glutamic acid (5 x 10(-5)M). These treatments did not enhance the efflux of [3H]tryptamine. The potassium-evoked release of [3H]5-HT was reduced by LSD (10(-5)M). LSD added alone in the superfusing fluid was without effect. The batrachotoxin-evoked release of [3H]5-HT was inhibited in the presence of tetrodotoxin (9 x 10(-6)M). The spontaneous release of [3H]5-HT and [3H]tryptamine was markedly reduced in the presence of a calcium-free medium containing cobalt (10 mM). A transient slight reduction in the spontaneous release of [3H]5-HT was observed in the presence of tetrodotoxin (9 x 10(-6)M). The local cooling of 5-HT cell bodies with a cryoelectrode induced a slight reversible decrease in [3H]5-HT release. These last two treatments were without significant effect on [3H]tryptamine efflux in superfusates. These results indicate that the release of [3H]5-HT endogenously formed from [3H]tryptophan is dependent on nerve activity and that this is not the case for [3H]tryptamine. The advantages of the isotopic approach for in vivo studies on the release of 5-HT are discussed.

Animals↗
PubMed2007

Phosphoramidate pronucleotides: a comparison of the phosphoramidase substrate specificity of human and Escherichia coli histidine triad nucleotide binding proteins.

To facilitate the delivery of nucleotide-based therapeutics to cells and tissues, a variety of pronucleotide approaches have been developed. Our laboratory and others have demonstrated that nucleoside phosphoramidates can be activated intracellularly to the corresponding 5'-monophosphate nucleotide and that histidine triad nucleotide binding proteins (Hints) are potentially responsible for their bioactivation. Hints are conserved and ubiquitous enzymes that hydrolyze phosphoramidate bonds between nucleoside 5'-monophosphate and an amine leaving group. On the basis of the ability of nucleosides to quench the fluorescence of covalently linked amines containing indole, a sensitive, continuous fluorescence-based assay was developed. A series of substrates linking the naturally fluorogenic indole derivatives to nucleoside 5'-monophosphates were synthesized, and their steady state kinetic parameters of hydrolysis by human Hint1 and Escherichia coli hinT were evaluated. To characterize the elemental and stereochemical effect on the reaction, two P-diastereoisomers of adenosine or guanosine phosphoramidothioates were synthesized and studied to reveal a 15-200-fold decrease in the specificity constant (kcat/Km) when the phosphoryl oxygen is replaced with sulfur. While a stereochemical preference was not observed for E. coli hinT, hHint1 exhibited a 300-fold preference for d-tryptophan phosphoramidates over l-isomers. The most efficient substrates evaluated to date are those that contain the less sterically hindering amine leaving group, tryptamine, with kcat and Km values comparable to those found for adenosine kinase. The apparent second-order rate constants (kcat/Km) for adenosine tryptamine phosphoramidate monoester were found to be 107 M-1 s-1 for hHint1 and 106 M-1 s-1 for E. coli hinT. Both the human and E. coli enzymes preferred purine over pyrimidine analogues. Consistent with observed hydrogen bonding between the 2'-OH group of adenosine monophosphate and the active site residue, Asp43, the second-order rate constant (kcat/Km) for thymidine tryptamine phosphoramidate was found to be 3-4 orders of magnitude smaller than that for uridine tryptamine phosphoramidate for hHint1 and 2 orders of magnitude smaller than that for E. coli hinT. Ara-A tryptamine phosphoramidate was, however, shown to be a good substrate with a specificity constant (kcat/Km) only 10-fold lower than the value for adenosine tryptamine phosphoramidate. Consequently, nucleoside phosphoramidates containing unhindered primary amines and either an alpha or beta 2'-OH group should be easily bioactivated by Hints with efficiencies rivaling those for the 5'-monophosphorylation of nucleosides by nucleoside kinases. The differential substrate specificity observed for human and E. coli enzymes represents a potential therapeutic rationale for the development of selective antibiotic phosphoramidate pronucleotides.

Amides↗
PubMed2006

[Analysis of the chemical drugs among structural isomer].

Drugs that have a pharmacological effect similar to legal drugs such as narcotics and stimulants are available in the market and widely used. 5-methoxy-N,N-di-iso-propyl-tryptamine (5MeO-DIPT) and alpha-methyl-tryptamine (AMT) were categorized as narcotics and were specified as legal drugs in April 2005, and also 2,5-dimethoxy-4-n-propylthiophenethylamine (4C-T-7) and N-methyl-alpha-ethyl-3,4-methylenedioxy-phenethylamine (MBDB) were categorized as narcotics and were specified as legal drugs in April 2006, in Japan. We are analyzing these chemical drugs by investigating the market research. It is recognized that during the analysis of chemical drugs, drugs that resemble a structural isomer of a target substance, such as 5MeO-DIPT and 5-methoxy-N,N-di-n-propyl-tryptamine (5MeO-DPT) or 4C-T-7 and 2,5-dimethoxy-4-iso-propylthiophenethylamine (4C-T-4), should be distinguished. The results of TLC, IR, GC-MS and HPLC analyses were compared. 5MeO-DIPT and 5MeO-DPT could be distinguished by TLC and HPLC analyses, but not by IR and GC-MS analysis. The drugs 4-hydroxy-N-methyl-N-iso-propyl-tryptamine (4HO-MIPT) and 4-hydroxy-N,N-di-ethyl-tryptamine (4HO-DET) or could not be distinguished. Moreover, the isomers of 4-hydroxy-N-methyl-N-n-propyl-tryptamine (4HO-MPT) was not found to be present. Thus, we have demonstrated that the chemical drug could be distinguished from each other, and we have also shown that NMR data is essential for the analysis.

Chromatography, High Pressure Liquid↗
PubMed1996

Neurotoxicity of free-radical-mediated serotonin neurotoxin in cultured embryonic chick brain neurons.

Exposure of serotonin (5-HT) to oxygen-derived free-radical-generating system, xanthine oxidase-hypoxanthine or to a Fenton reaction results in the formation of the neurotoxin, tryptamine-4,5-dione. In cultured embryonic chick brain neurons, incubation of tryptamine-4,5-dione or its ethyl carbonate derivative resulted in a dose-dependent neurotoxicity (1-100 microM). The addition of sulfhydryl compound, glutathione at 2 or 10 microM significantly enhanced the toxicity induced by 10 microM tryptamine-4,5-dione. On the contrary, glutathione at 10 microM decreased the neurotoxic effect caused by 10 microM 5,6- and 5,7-dihydroxytryptamine in the cultured neurons. The toxicity resulted from 5,6- and 5,7-dihydroxytryptamine could be fully prevented by a 5-HT uptake inhibitor, fluoxetine. However, the toxicity caused by tryptamine-4,5-dione and glutathione conjugate could not be blocked by fluoxetine (10 or 100 microM) or by a glutathione transferase inhibitor, boric acid/serine. The results indicate a different molecular mechanism among 5-HT derived neurotoxins and suggest that tryptamine-4,5-dione and/or its glutathione conjugate would cause neuronal damage, if they are formed in vivo.

5,6-Dihydroxytryptamine↗
PubMed1989

Lesion-induced reductions in trace amine accumulation: dependence on MAO inhibitor pretreatment.

Striatal amine levels were measured six weeks after unilateral injections of 6-OHDA (8 micrograms) into the substantia nigra in male Wistar rats pretreated with monoamine oxidase inhibitors. After (-) deprenyl.HCl pretreatment (2 mg.kg-1 SC 2hr), beta-phenylethylamine, m- and p-tyramine ipsilateral to the 6-OHDA lesion decreased to 50, 18 and 25% of contralateral levels. DA, DOPAC and HVA also decreased on the lesioned side. Ipsilateral concentrations of tryptamine, 5-HT, 5-HIAA, p-tyrosine and L-tryptophan concentrations were equivalent to contralateral values in this condition. In animals pretreated with pargyline.HCl (200 mg.kg-1 IP 2hr) m- and p-tyramine and tryptamine ipsilateral to the lesion decreased to 48, 59 and 57% of contralateral levels. Ipsilateral DA decreased to 26% of the contralateral value. Under these conditions no change in concentrations of beta-phenylethylamine or of the above acid metabolites or amino acids was observed. The masking of lesion-induced changes in beta-phenylethylamine by pargyline is attributed to the lipophilic nature of of this molecule and consequent diffusion of this amine from other areas after maximal monoamine oxidase inhibition. Conversely the failure to demonstrate lesion-induced changes in tryptamine with (-) deprenyl pretreatment is attributed to the nonselectivity of monoamine oxidase for tryptamine and activity of monoamine oxidase A under these conditions. These results indicate that for further assessment of lesion-induced changes in beta-phenylethylamie and of tryptamine the respective (-) deprenyl and pargyline pretreatments used in this study are appropriate.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMedDate not supplied

Functional and radioligand binding characterization of rat 5-HT6 receptors stably expressed in HEK293 cells.

We have stably expressed the rat 5-HT6 receptor in HEK293 cells at a density of > 2 pmol/mg protein, as determined in equilibrium binding studies with [3H]-LSD and [3H]-5-HT and compared the affinity of a range of compounds in competition binding experiments with either [3H]-LSD or [3H]-5-HT as radioligand. A variety of tryptamine derivatives were tested and showed a significantly higher affinity when the 5-HT6 receptor was labelled with [3H]-5-HT, whereas ergoline compounds and several antagonists had higher affinities when [3H]-LSD was used as radioligand. Subsequently we examined the ability of LSD, 5-HT and a number of tryptamine derivatives to stimulate cAMP accumulation in order to determine their agonist potency and efficacy. We observed the following rank order of potency: LSD > omega-N-methyl-5-HT approximately bufotenine approximately 5- methoxytryptamine > 5-HT > 2-methyl-5-HT approximately 5-benzyloxytryptamine approximately tryptamine > 5-carboxamidotryptamine > > 5-HTQ. LSD, lisuride, 2-methyl-5-HT, tryptamine and 5-benzyloxytryptamine behaved as partial agonists relative to 5-HT. The rank order of potency of the tryptamine compounds correlated well with their affinities determined in binding assays. In addition, we have tested a number of antagonists in this system (rank order of potency: methiothepin, clozapine, mianserin and ritanserin). This characterization of the pharmacological properties of recombinant 5-HT6 receptor will facilitate the identification of 5-HT6 receptor-mediated responses in physiological systems.

Adenylyl Cyclases↗
PubMed1995

Vascular 5-HT1-like receptors mediating vasoconstriction and vasodilatation: their characterization and distribution in the intact canine cardiovascular system.

1. In anaesthetized dogs, intra-left atrial administration of 5-hydroxytryptamine (5-HT) and selected tryptamine analogues (5-carboxamidotryptamine, 5-CT; 5-methyl tryptamine, 5-MT; alpha-methyl 5-hydroxytryptamine, alpha-HT; sumatriptan, Sum) in the presence of ketanserin and MDL72222 (5-HT2 and 5-HT3 receptor antagonists, respectively), produced dose-related changes in carotid, coronary and renal vascular conductance mediated by vascular 5-HT1-like receptors. 2. In the carotid vascular bed, 5-HT, 5-MT, alpha-HT and Sum were vasoconstrictors with a rank order of potency (comparing ED50 values) of 5-HT = Sum > 5-MT > alpha-HT. By contrast in this vascular bed, 5-CT was a potent vasodilator. 3. In the coronary vascular bed, 5-HT, 5-CT, 5-MT and alpha-HT were vasodilators with a rank order of potency (comparing ED50 values) of 5-CT > 5-HT > 5-MT > alpha-HT. In this vascular bed, Sum was without effect. 4. In the renal vascular bed, 5-HT, 5-CT, 5-MT, alpha-HT and Sum were vasoconstrictors with a rank order of potency (comparing ED50 values) of 5-CT > 5-HT > Sum > 5-MT > alpha-HT. 5. The coronary (and carotid) vasodilator responses to 5-CT were antagonized by the 5-HT1-like receptor antagonists, spiperone (1 mg kg-1) and methiothepin (0.1 mg kg-1), whereas the renal vasoconstrictor responses to this tryptamine analogue were antagonized only by methiothepin. 6. It is concluded from these studies that agonist finger-printing in vivo, using tryptamine analogues,identifies and confirms the functional presence of at least two pharmacologically distinct subtypes of the 5-HT1-like receptor in the intact canine cardiovascular system. These two subtypes are located on the vascular smooth muscle and mediate direct vasoconstriction and vasodilatation responses in vivo.7. In addition, these studies confirm that the distribution of these subtypes within the major vascular beds, shows a marked heterogeneity. The carotid vascular responses to the tryptamine analogue sindicate the presence of both the vasodilator and the vasoconstrictor subtypes. The coronary vascular responses to these analogues are, however, consistent with presence of the vasodilator subtype, only. By contrast, the renal vascular responses to these analogues indicates only the presence of the vasoconstrictor subtype.

Animals↗
PubMedDate not supplied

Photomodulation of the melanocyte cell cycle by indoleamines.

Melanocytes are photoresponsive cells which respond to varying doses of UV exposure in the G2 phase of the cell cycle by prominent dendricity. This photoresponse is related to indoleamine light sensitivity. The present study highlights the role of indoleamines in the photomodulation of the melanocyte cell cycle. The study was conducted on 40 whole-skin organ cultures taken from the marginal zone of vitiligo. Twenty organ cultures were subjected to G2-phase arrest, while 20 were incubated in tryptamine. The organ cultures were incubated in the dark, exposed to a pulse of 120 s UV at 2 h of incubation and harvested 3 and 6 h after UV exposure. It has been reported that the photosensitive enzymes N-acetyl transferase (NAT) and hydroxyindole-o-methyl transferase (HIOMT) are activated during the G2 phase. The conversion of serotonin to melatonin is inhibited by UV exposure as seen at 3 h. This activity recovers on continued dark incubation 6 h after UV exposure. On incubation with tryptamine, UV exposure results in utilisation of tryptamine as seen by prominent indoleamine positivity. Three hours after UV exposure, there is 75% dendricity indicating G2 phase traverse. There is a corresponding high serotonin positivity with a low melatonin positivity. This is reversed following 6 h of dark incubation with high melatonin positivity indicating reactivation of NAT and HIOMT. This is accompanied by a doubling of the melanocyte number due to mitotic traverse and an arrest in G1 phase with low utilisation of tryptamine. Thus tryptamine is utilised by melanocytes on UV exposure to be synchronised and traversed into G2 phase activating the photosensitive enzymes NAT and HIOMT. When followed by a dark phase, melatonin accumulates to traverse the melanocytes through M-phase of the cell cycle with doubling of the cell number. Thus the uptake and metabolisation of indoleamine precursors photomodulate the melanocyte cell cycle on UV exposure.

Acetylserotonin O-Methyltransferase↗
PubMed1999

F 11356, a novel 5-hydroxytryptamine (5-HT) derivative with potent, selective, and unique high intrinsic activity at 5-HT1B/1D receptors in models relevant to migraine.

F 11356 (4-[4-[2-(2-aminoethyl)-1H-indol-5-yloxyl]acetyl]piperazinyl-1-yl] ben zonitrile) was designed to take advantage of the superior potency and efficacy characteristics of 5-hydroxytryptamine (5-HT) compared with tryptamine at 5-HT1B/1D receptors. F 11356 has subnanomolar affinity for cloned human and nonhuman 5-HT1B and 5-HT1D receptors, and its affinity for 5-HT1A and other 5-HT receptors, including the 5-ht1F subtype, is 50-fold lower and micromolar, respectively. In C6 cells expressing human 5-HT1B or human 5-HT1D receptors, F 11356 was the most potent compound in inhibiting forskolin-induced cyclic AMP formation (pD2 = 8.9 and 9.6), and in contrast to tryptamine and derivatives, it produced maximal enhancement of [35S]guanosine-5'-O-(3-thio)triphosphate-specific binding equivalent to 5-HT. F 11356 was equipotent to 5-HT (pD2 = 7.1 versus 7.2) and more potent than tryptamine derivatives in contracting rabbit isolated saphenous vein. In isolated guinea pig trigeminal ganglion neurons, F 11356 was more potent (pD2 = 7.3 versus 6.7) and induced greater increases in outward hyperpolarizing Ca2+-dependent K+ current than sumatriptan. In anesthetized pigs, F 11356 elicited highly cranioselective, more potent (from 0.16 microgram/kg i.v.) and greater carotid vasoconstriction than tryptamine derivatives. Decreases in carotid blood flow were observed in conscious dogs from 0.63 mg/kg oral F 11356 in the absence of changes in heart rate or behavior. Oral activity was confirmed when hypothermic responses were elicited in guinea pigs (ED50 = 1.6 mg/kg), suggesting that F 11356 also accesses the brain. F 11356 thus is a selective, high-potency agonist at 5-HT1B/1D receptors, which distinguishes itself from tryptamine and derivatives in exerting high intrinsic activity at these receptors in vascular and neuronal models relevant to migraine.

Animals↗
PubMed1975

Characterization by cyproheptadine of the dopamine-induced contraction in canine isolated arteries.

Spirally cut strips of isolated canine femoral and carotid arteries were used to characterize the vasoconstrictor effect of dopamine. A serotonin antagonist, cyproheptadine, 10- minus 7, 3 X 10- minus 7 and 10-minus 6 M, inhibited dopamine (pA2 = 7.46 plus or minus 0.11), tryptamine (pA2 = 7.38 plus or minus 0.09) and serotonin-induced contractions (pA2 = 7.59 plus or minus 0.09). Cyproheptadine shifted the threshold concentration of dopamine 2 log units to the right without altering norepinephrine response. In protection experiments, preincubation with serotonin (10-minus 5 M) for 10 minutes protected serotonin and tryptamine receptors from cyproheptadine (3 X 10-minus 7 M) and phenoxybenzamine (10-minus 6 M) blockade. Serotonin cross-protected dopamine receptors also. Reciprocally dopamine (10-minus 4 M) protected its own receptors as well as those for serotonin and tryptamine. Norepinephrine did not afford any protection of dopamine, serotonin or tryptamine receptors but did protect its own receptors from phenoxybenzamine blockade. The attempt to characterize the receptor subserving dopamine-induced contraction failed to confirm a relationship between dopamine and alpha adrenoceptors. Since dopamine, tryptamine and serotonin, unlike norepinephrine, were sensitive to cyproheptadine blockade, dopamine-induced contraction appeared to be mediated by a receptor closely related to serotonin receptors. Therefore, alpha adrenoceptors may not be exclusively involved in the vasoconstriction evoked by dopamine on canine vasculature.

Animals↗
PubMed1980

[Interaction of indoleamines with serotonergic receptors of brain synaptosomes].

A procedure involving gel-filtration was used to study the binding of serotonin and tryptamine to the post-synaptic serotoninergic receptors of mouse brain synaptosomes. It was shown that the serotoninergic receptors bind tryptamine to a larger extent than serotonin--6,50 +/- 0,17 and 3,70 +/- 0,07 nmol/mg of protein, respectively. There is a direct correlation between the rate of tryptamine binding to the receptors and the protein content in synaptosomal preparations within the interval of 0,3-1,25 mg. The optimal binding of tryptamine to the receptors occurs at pH 10,1. The shift in pH to the acidic region sharply decreases the rate of binding. An increase in the ionic strength of the medium causes a decrease of tryptamine binding to the receptors, which suggests a participation of electrostatic forces in the interaction of indolamines with serotoninergic receptors.

Animals↗
PubMed1987

Effect of phorbol 12-myristate 13-acetate (PMA) on agonist-induced arachidonate release and 5-hydroxytryptamine secretion in human platelets. Dependence of effects on agonist type and time of incubation with PMA.

We have previously demonstrated synergistic potentiation of secretion by phorbol 12-myristate 13-acetate (PMA) and platelet agonists such as thrombin and the thromboxane mimetic, U46619, with short (less than 2 min) pre-incubations of PMA, despite inhibition of agonist-induced [Ca2+]i mobilization and arachidonate/thromboxane release. In this study, the effect of PMA on 5-hydroxytryptamine secretion in relation to arachidonate/thromboxane B2 release induced by collagen as well as the 'weak agonists', ADP, adrenaline and platelet-activating factor (PAF), was investigated using human platelet-rich plasma. Short incubations (10-30 s) with PMA (400 nM) before agonist addition caused an inhibition (60-100%) of 5-hydroxy[14C]tryptamine secretion and thromboxane B2 formation in response to maximally effective doses of ADP (10 microM), adrenaline (10 microM) and PAF (0.5 microM) but potentiated collagen-induced 5-hydroxy[14C]tryptamine secretion and [3H]arachidonate/thromboxane release. However, a longer pre-incubation with PMA (5 min) caused a significant reduction (20-50%) in the extent of collagen-induced 5-hydroxy[14C]tryptamine secretion and thromboxane B2 formation as seen earlier with thrombin, although collagen-induced [3]arachidonate release was still unaffected. Pretreatment of platelets with the cyclo-oxygenase inhibitor, indomethacin (10 microM), abolished 5-hydroxy[14C]tryptamine secretion in response to the weak agonists and reduced collagen (2.5-10 micrograms/ml) -induced secretion by 50-90%, depending on the collagen concentration. Addition of PMA (400 nM) 10 s before these agonists in indomethacin-treated platelets resulted in synergistic interactions between agonist and PMA leading to enhanced 5-hydroxy[14C]tryptamine secretion, although this was notably less than the synergism observed previously between thrombin and PMA or U46619 and PMA. The results suggest that the effect of short incubations with PMA on 5-hydroxytryptamine secretion induced by 'thromboxane-dependent' agonists, such as those examined in this study, is determined by the effect on agonist-induced thromboxane synthesis. However, when endogenous thromboxane synthesis is blocked, weak agonists as well as collagen can synergize with PMA at potentiating 5-hydroxytryptamine secretion, albeit to a weaker extent than thrombin or U46619. The results also suggest that PMA has differential effects on arachidonate release induced by collagen and thrombin.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1979

Effects of collagen, ionophore A23187 and prostaglandin E1 on the phosphorylation of specific proteins in blood platelets.

Human platelets that had been preincubated with 5-hydroxy[(3)H]tryptamine and [(32)P]P(i) were stirred with various agents; the secretion of 5-hydroxy[(3)H]tryptamine from platelet granules and the radioactivity of platelet [(32)P]phosphopolypeptides separated by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis were then measured. Exposure of the platelets to collagen fibres or ionophore A23187 selectively increased the phosphorylation of polypeptides with apparent mol.wts. of 47000 (P47) and 20000 (P20) by approx. 3-fold, in association with the release of 5-hydroxy[(3)H]tryptamine. The 47000-mol.wt. phosphopolypeptide (P47) was clearly separated from platelet actin by the electrophoresis system used. Prostaglandin E(1), which inhibits platelet function by increasing platelet cyclic AMP, decreased the phosphorylation of polypeptides caused by collagen as well as the release of 5-hydroxy[(3)H]tryptamine. Prostaglandin E(1) also selectively increased the phosphorylation of distinct polypeptides with apparent mol.wts. of 24000 (P24) and 22000 (P22) by approx. 2-fold. As the phosphorylation reactions caused by collagen are probably mediated by an increase in Ca(2+) concentration in the platelet cytosol and may have a role in the release reaction [Haslam & Lynham (1977) Biochem. Biophys. Res. Commun.77, 714-722; (1978) Thromb. Res.12, 619-628], we suggest that a cyclic AMP-dependent phosphorylation of the 24000- and/or 22000-mol.wt. polypeptides caused by prostaglandin E(1) may initiate processes that decrease the Ca(2+) concentration in the cytosol, so inhibiting both the Ca(2+)-dependent phosphorylation reactions and the release reaction. Treatment of platelets with prostaglandin E(1) did not inhibit the increased phosphorylation of polypeptides with apparent mol.wts. of 47000 and 20000 (P47 and P20) caused by ionophore A23187, which may therefore short-circuit cyclic AMP-dependent mechanisms that decrease the Ca(2+) concentration in the platelet cytosol. As prostaglandin E(1) did inhibit the release of 5-hydroxy[(3)H]tryptamine by ionophore A23187, cyclic AMP may also inhibit the release reaction by additional mechanisms.

Anti-Bacterial Agents↗
PubMed1988

Responses to 5-hydroxytryptamine evoked in the hemisected spinal cord of the neonate rat.

1. Superfusion of isolated hemisected spinal cord from neonate rats with 5-hydroxytryptamine (5-HT) (10(-6) to 10(-3) M) evoked concentration-related depolarizations. The maximal depolarization elicited by a concentration of 10(-4) M was 1.0 +/- 0.1 mV (mean +/- s.e.mean, n = 30). Noradrenaline in a similar range of concentrations also elicited depolarizations. 2. The depolarizations probably originate in motoneurones as a result of direct interaction of the amines with these cells, since responses were unaltered by tetrodotoxin (10(-7) M) or Ca2+-free/Mg2+-rich medium. 3. 5-Carboxamidotryptamine (5-CT), S(+)-alpha-methyl-5-hydroxytryptamine (alpha-Me5-HT) and 5-methoxytryptamine (5-MeOT) evoked similar depolarizations to 5-HT. Tryptamine evoked depolarizations of smaller maximal amplitude. 5-Hydroxytryptophan, 2-methyl-5-hydroxytryptamine, 8-hydroxy-2-(di-N-propylamino) tetralin hydrobromide (8-OH-DPAT) and 5-methoxy-3-[1,2,3,6-tetrahydro-4-pyridinyl]-1-H-indole succinate (RU 24969) had no depolarizing action. 4. Concentration-response (CR) curves were determined for 5-HT, 5-CT, alpha-Me5-HT, 5-MeOT and tryptamine. The ED50 value for 5-HT was 20.5 +/- 1.2 microM. The equipotent molar ratios (EPMRs) for 5-CT and alpha-Me5-HT were close to unity, while 5-MeOT was approximately 3 times and tryptamine 13 to 14 times less potent than 5-HT. 5. The relative agonist potency of 5-HT with respect to other tryptamine analogues capable of depolarizing motoneurones was increased when 5-HT uptake was blocked by citalopram (10(-7) M). In the presence of citalopram, 5-HT was 2.7 times more potent than alpha-Me5-HT and 16.9 times more potent than 5-CT. The apparent order of potency was 5-HT greater than alpha-Me5-HT greater than 5-CT (greater than 5-MeOT much greater than tryptamine). 6. The monoamine oxidase inhibitor, pargyline (5 x 10(-4) M), had no effect on depolarizations to 5-HT, 5-CT or alpha-Me5-HT. 7. Methiothepin, 1 alpha H, 3 alpha, 5H-tropan-3-yl-3,5-dichlorobenzoate methanesulphonate (MDL 72222) and [3 alpha-tropanyl]-1H-indole-3-carboxylic acid ester hydrochloride (ICS 205-930) had no effect on 5-HT depolarizations elicited in motoneurones. Ketanserin (0.75 x 10(-7) M to 10(-6) M) showed modest antagonistic action and depressed maximal response amplitude; the pIC50 was 6.5. 8. Methysergide (10-8 to 10- 7M) was a potent antagonist of responses to 5-HT. CR curves were displaced to the right and flattened in the presence of the antagonist. The pIC5o assessed from the effect on depolarizations evoked by 5-HT 1O-4M was 7.5. 9. It is concluded that 5-HT acts directly to depolarize mammalian spinal motoneurones through receptors that are also activated by 5-CT, alpha-MeS-HT and 5-MeOT and are blocked by methysergide. The receptor profile, although not 5-HT3-like, does not clearly coincide with that for either 5-HT1-like or 5-HT2 receptors.

Animals↗
PubMed1981

Effect of tryptophan administration on tryptophan, 5-hydroxyindoleacetic acid and indoleacetic acid in human lumbar and cisternal cerebrospinal fluid.

Tryptophan 5-hydroxyindoleacetic acid and indoleacetic acid were measured in cerebrospinal fluid taken during pneumoencephalography from patients, some of whom took a 3 g or 6 g tryptophan load at various times before. Measurements were made on both lumbar and cisternal cerebrospinal fluid and the results showed similarities between indoleamine metabolism in human brain and spinal cord. Our data suggested that (1) the blood-brain barrier active transport system for tryptophan is not far from saturation with tryptophan and the rate-limiting enzyme in 5-hydroxytryptamine (5HT) synthesis, tryptophan hydroxylase, is about half saturated. Therefore, both 3 g and 6 g tryptophan loads produced the same maximum rise in 5HT synthesis of just under 100%, (2) tryptamine differs from 5HT in two respects. It is more sensitive to changes in tryptophan availability than 5HT and the 6 g load increased brain tryptamine metabolism more than the 3 g load; also some of the tryptamine in brain is derived from peripheral sources and diffuses from blood to brain, (3) although the brain tryptamine content is much lower than that of 5HT, its rate of metabolism as indicated by CSF metabolite levels is not. In controls the rate of tryptamine metabolism is 15% of the rate of 5HT metabolism and this can increase to 40% after a 6 g tryptophan load.

Adolescent↗
PubMed1977

CNS monoamine metabolism in bipolar affective disorder. Evaluation using a peripheral decarboxylase inhibitor.

Carbidopa, a decarboxylase inhibitor that does not cross the blood-brain barrier, inhibits the peripheral synthesis of nor-adrenaline, serotonin, and tryptamine. By reducing the peripheral component of end-products of these amines in urine, a more accurate assessment of central nervous system (CNS) amine metabolism is provided. Urinary 5-hydroxyindoleacetic acid (5-HIAA), tryptamine, and 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured over ten days in ten normal controls and eight bipolar depressives. After a three-day baseline period, carbidopa, 100 mg three times a day, was given for seven days. While the patients tended to excrete less MHPG in the baseline period, these differences became somewhat larger, and statistically significant when peripheral contributions were reduced with carbidopa. While carbidopa resulted in striking inhibition of tryptamine excretion, and smaller decreases in the excretion of 5-HIAA and MHPG, evidently from storage pools, there were no significant differences in degree of inhibition between patients and controls. Absolute values of 5-HIAA and tryptamine were similar for both groups, during the baseline and again with carbidopa. These results after carbidopa are compatible with a central catecholaminergic deficit in bipolar depressives and the use of urinary MHPG as an index of CNS catecholamine function.

Adolescent↗
PubMed1989

High performance liquid chromatographic analysis of time-dependent changes in urinary excretion of indoleamines following tryptophan administration.

Analytical conditions of prepurification extraction and HPLC separation were optimized for determination of urinary serotonin and tryptamine. Under optimal conditions, serotonin, tryptamine and an internal standard were extracted with 15% v/v n-propanol in diethyl ether from urine samples alkalized with a phosphate buffer (0.75 mol/L, pH 10.0), and then they were re-extracted into an HCl solution (0.1 mol/L). Purified indoleamines were simultaneously separated by reversed-phase ion-pair HPLC with native fluorescence detection. Urinary serotonin and tryptamine were selectively determined within about 45 min per sample for the whole procedure. Analytical recovery, reproducibility and detection sensitivity were satisfactory for pursuing time-dependent changes in indoleamine levels. Urinary excretion profiles of serotonin and tryptamine in subjects dosed with L-tryptophan were successfully analyzed by our method.

Adult↗
PubMed1991

Secondary metabolite biosynthesis in cultured cells of Catharanthus roseus (L.) G. Don immobilized by adhesion to glass fibres.

Suspension-cultured cells of Catharanthus roseus (L.) G. Don were immobilized on glass fibre mats and cultivated in shake flasks. The highly-aggregated immobilized cells exhibited a slower growth rate and accumulated reduced levels of tryptamine and indole alkaloids, represented by catharanthine and ajmalicine, in comparison to cells in suspension. The increased total protein synthesis in immobilized cells suggests a diversion of the primary metabolic flux toward protein biosynthetic pathways and away from other growth processes. In-vitro assays for the specific activity of tryptophan decarboxylase (TDC) and tryptophan synthase (TS) suggest that the decreased accumulation of tryptamine in immobilized cells was due to reduced tryptophan biosynthesis. The specific activity of TDC was similar in immobilized and suspension-cultured cells. However, the expression of TS activity in immobilized cells was reduced to less than 25% of the maximum level in suspension-cultured cells. The reduced availability of a free tryptophan pool in immobilized cells is consistent with the reduced TS activity. Reduced tryptamine accumulation, however, was not responsible for the decreased accumulation of indole alkaloids in immobilized cells. Indole alkaloid accumulation increased to a similar level in immobilized and suspension-cultured cells only after the addition of exogenous secologanin to the culture medium. The addition of tryptophan resulted in increased accumulation of tryptamine, but had no effect on indole alkaloid levels. Reduced biosynthesis of secologanin, the monoterpenoid precursor to indole alkaloids, in immobilized cells is suggested. Immobilization does not appear to alter the activity of indole alkaloid biosynthetic enzymes in our system beyond, and including, strictosidine synthase.

Alkaloids↗