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PubMed1974

Tryptamine receptors in rat pulmonary artery.

Tryptamine and 5-hydroxytryptamine (5-HT) are equipotent in contracting spiral strips of rat isolated pulmonary artery, in doses between 5 and 20 mug. These 5-HT receptors are blocked by low concentrations (c. 10(-9) M) of both methysergide and morphine. In rat isolated lung perfused via the pulmonary circulation, 5-HT caused increases in perfusion pressure which were also antagonized by methysergide and by morphine. These vascular 5-HT receptors cannot therefore be classified as M or D receptors and, furthermore, are different from those 5-HT receptors mediating release of spasmogens from rat isolated lungs.

Animals↗
PubMed1975

Atypical tryptamine receptors in sheep pulmonary vein.

Both the pulmonary artery and vein of the sheep contracted dose-dependently to histamine, carbamoylcholine, prostaglandin F2a, noradrenaline and bradykinin and relaxed in the presence of isoprenaline or prostaglandin E1. 2 The effect of 5-hydroxytryptamine (5-HT) on the artery was consistently to produce dose-dependent contractions without tachyphylaxis. The effect on the vein was biphasic. 5HT 5 X 10(-10) to 5 X 10(-8) M relaxed the partially constricted vein. 5-HT 10(-7) to 10(-6) m caused brief venoconstriction followed by relaxation. 5-HT greater than 10(-6) M caused dose-related contraction of the vein. 3 Methysergide effectively blocked the contractile response of the artery to 5-HT, but only weakly inhibited the contractions of the vein (dose-ratio less than 20). 4 Each of ten antagonists tested failed to inhibit the 5-HT-induced relaxation of the vein. Sheep pulmonary vein possesses tryptamine receptors which mediate relaxation and which are not of the classicl M- or D-type. These receptors appear not to be involved directly or indirectly with responses to acetylcholine, catecholamines, histamine or prostaglandins.

Animals↗
PubMed1991

Further characterization, by use of tryptamine and benzamide derivatives, of the putative 5-HT4 receptor mediating tachycardia in the pig.

1. It has recently been shown that the tachycardic response to 5-hydroxytryptamine (5-HT) in the anaesthetized pig, being mimicked by 5-methoxytryptamine and renzapride and blocked by high doses of ICS 205-930, is mediated by the putative 5-HT4 receptor. In the present investigation we have further characterized this receptor. 2. Intravenous bolus injections of the tryptamine derivatives, 5-HT (3, 10 and 30 micrograms kg-1), 5-methoxytryptamine (3, 10 and 30 micrograms kg-1) and alpha-methyl-5-hydroxytryptamine (alpha-methyl-5-HT; 3, 10, 30 and 100 micrograms kg-1), resulted in dose-dependent increases in heart rate of, respectively, 25 +/- 2, 48 +/- 3 and 68 +/- 3 beats min-1 (5-HT; n = 35); 15 +/- 1, 32 +/- 2 and 57 +/- 3 beats min-1 (5-methoxytryptamine; n = 30); 6 +/- 4, 18 +/- 6, 34 +/- 6 and 64 +/- 11 beats min-1 (alpha-methyl-5-HT; n = 3). 3. The increases in heart rate following i.v. administration of certain substituted benzamide derivatives were genereally less marked and not dose-dependent: 1 + 5, 11 + 3 and 10 + 5 beats min1- after 300, 1000 and 3000,jgkg' of metoclopramide, respectively, (n = 8); 21 + 4, 19 + 2 and 2 + 2 beats min'- after 100, 300 and lOOOIpgkg1- of cisapride, respectively, (n = 5); 6 + 2, 14 + 2, 37 + 6, 43 + 8 and 34 + 10 beats min- after 10, 30, 100, 300 and lOOOjigkg' of zacopride, respectively, (n = 6); and 1 + 1, 2 + 1 and 5 + 2 beats min- 1 after 300, 1000 and 3000 pg kg' of dazopride, respectively, (n = 4). These drugs behaved as partial agonists, antagonizing the responses to 5-HT and 5-methoxytryptamine dosedependently. 4. The 5-HT3 receptor agonist 1-phenyl-biguanide (100, 300 and lOOOpgkg-1) induced only slight increases in heart rate of 1 + 1, 6 + 2 and 11 + 1 beats min 1, respectively, (n = 3). These effects were not antagonized by the selective 5-HT3 receptor antagonist granisetron (3mgkg-1). In addition, 1-phenylbiguanide (1000,pg kg- 1) did not modify the tachycardia induced by either 5-HT- or 5- methoxytryptamine. 5. High doses (3mg kg- 1) of ICS 205-930, a 5-HT3 receptor antagonist with an indole group and devoid of effects on porcine heart rate per se, antagonized the stimulatory effects of 5-HT, 5-methoxytryptamine, alpha-Me-5-HT, metoclopramide, cisapride, zacopride, dazopride and 1-phenyl-biguanide. However, the 5-HT2 receptor antagonist ketanserin (0.5 mg kg- 1), the 5-HT3 receptor antagonists granisetron (3mg kg- 1) and MDL 72222 (3mg kg- ') and the dopamine D2 receptor antagonist domperidone (3 mg kg- 1) had no antagonist activity. 6. The above results support our contention that 5-HT, 5-methoxytryptamine, alpha-Me-5-HT and the substituted benzamide derivatives increase porcine heart rate by a direct action on the cardiac pacemaker, via the activation of a putative 5-HT4 receptor. The pharmacological profile of this novel 5-HT receptor is similar (neurones from mouse brain colliculi and human heart) or, perhaps, even identical (guinea-pig cholinergic neurones) to other putative 5-HT4 receptors.

5-Methoxytryptamine↗
PubMed1996

Kinetic studies of N-allenic analogues of tryptamine as monoamine oxidase inhibitors.

A series of N-allenic analogues of tryptamine in which the side chain is located at the 2 position of the indole ring, but which differed in the ring and side-chain nitrogen substituents, were assayed kinetically as MAO A and MAO B inhibitors. All the compounds studied were mechanism-based inhibitors. The kinetic constants of each inhibition step Ki and ki, were determined for both MAO A and B. The data obtained indicated that these allenic derivatives show a greater selectivity and potency towards MAO A as inhibitors than the corresponding acetylenic derivatives.

Animals↗
PubMed1997

Interaction of tryptamine and ergoline compounds with threonine 196 in the ligand binding site of the 5-hydroxytryptamine6 receptor.

We examined the ligand-binding site of the 5-hydroxytryptamine6 (5-HT6) receptor using site-directed mutagenesis. Interactions with residues in two characteristic positions of trans-membrane region V are important for ligand binding in several bioamine receptors. In the 5-HT6 receptor, one of these residues is a threonine (Thr196), whereas in most other mammalian 5-HT receptors, the corresponding residue is alanine. After transient expression in human embryonic kidney 293 cells, we determined the effects of the mutation T196A on [3H]d-lysergic acid diethylamide (LSD) binding and adenylyl cyclase stimulation. This mutation produced a receptor with a 10-fold reduced affinity for [3H]LSD and a 6-fold reduced affinity for 5-HT. The potency of both LSD and 5-HT for stimulation of adenylyl cyclase was also reduced by 18- and 7-fold, respectively. The affinity of other N1-unsubstituted ergolines (e.g., ergotamine, lisuride) was reduced 10-30 fold, whereas the affinity of N1-methylated ergolines (e.g., metergoline, methysergide, mesulergine) and other ligands, such as methiothepine, clozapine, ritanserin, amitriptyline, and mainserin, changed very little or increased. This indicates that in wild-type 5-HT6 receptor, Thr196 interacts with the N1 of N1-unsubstituted ergolines and tryptamines, probably forming a hydrogen bond. Based on molecular modeling, a serine residue in transmembrane region IV of the 5-HT2A receptor has previously been proposed to interact with the N1-position of 5-HT. When the corresponding residue of the 5-HT6 receptor (Ala154) was converted to serine, no change in the affinity of twelve 5-HT6 receptor ligands or in the potency of 5-HT and LSD could be detected, suggesting that this position does not contribute to the ligand binding site of the 5-HT6 receptor.

Amino Acid Sequence↗
PubMed2001

Interactions of tryptamine derivatives with serotonin transporter species variants implicate transmembrane domain I in substrate recognition.

The serotonin (5-hydroxytryptamine, 5-HT) transporter (SERT) is responsible for the inactivation of synaptic 5-HT and is also a target for multiple psychostimulants. Despite the critical role of SERT in 5-HT inactivation and psychostimulant response, many aspects of the transporter's recognition of ligands are poorly defined. We took advantage of sequence divergence of SERT species variants to identify structural determinants of substrate recognition. Tryptamine derivatives with substitutions at the 4 and 7 positions on the phenyl ring, the indole nitrogen, and the beta position show up to 40-fold potency differences for inhibiting [(3)H]5-HT transport in cells transfected with either human or Drosophila melanogaster SERT cDNAs. Species selectivities of these derivatives were largely recapitulated in antagonist binding. Human/D. melanogaster SERT chimera studies implicated the first two SERT transmembrane domains (TMDs) in the potency of the indole nitrogen-substituted compounds N-isopropyltryptamine (NIT), 5-methoxy-N-isopropyltryptamine (5-MNIT), and the 7-substituted compound 7-benzyloxytryptamine (7BT). Potency differences of analogs with substitutions at the 4 and beta positions are influenced by sequences distal to this region. Within TMD I-II, species-scanning mutagenesis implicated a single residue (Y95 in human SERT, F90 in D. melanogaster SERT) in the recognition of NIT, 5-MNIT, and 7BT. Remarkably, this is the same site we established previously in species-specific recognition of the antagonists citalopram and mazindol. These findings support a critical role for TMD I residues in defining shared aspects of SERT substrate and antagonist recognition.

Animals↗
PubMed2004

Direct measurement of energy thresholds to conformational isomerization in tryptamine.

Stimulated emission pumping (SEP)-hole filling spectroscopy and SEP-induced population transfer spectroscopy have been used to place narrow bounds on the energy thresholds for isomerization between individual reactant-product isomer pairs involving the seven conformational minima of tryptamine. The thresholds for isomerizing conformer A to all six other conformations divided into three groups at 750 wavenumbers (cm-1)(A-->B, F), 1000 cm-1 [A-->C(2)], and 1280 to 1320 cm-1 [A-->D, E, and C(1)]. The appearance of the first band and the absence of the band below it were used to place upper and lower bounds to the barrier heights for each process. The thresholds for A-->B and B-->A isomerizations were also combined to determine the relative energies of these two lowest energy minima. The combined data from all X-->Y isomerizations identify important isomerization pathways on the potential energy surface linking the minima.

Chemical Phenomena↗
PubMed1982

Precursors and metabolites of phenylethylamine, m and p-tyramine and tryptamine in human lumbar and cisternal cerebrospinal fluid.

Phenylacetic acid, p-hydroxyphenylacetic acid, m-hydroxyphenylacetic acid, phenylalanine, indoleacetic acid, 5-hydroxyindoleacetic acid and tryptophan were measured in lumbar and cisternal cerebrospinal fluid (CSF) taken during pneumoencephalography. The data suggest that the concentration of the acid metabolites of the trace amines tryptamine, phenylethylamine, p-tyramine and m-tyramine in lumbar CSF are influenced by the system that transports these acids out of CSF. In cisternal CSF this mechanism does not operate and more information can be obtained on the metabolism of the parent amines in the CNS. Our data indicate that (1) m-tyramine is relatively unimportant quantitatively (2) the rate of metabolism of phenylethylamine in human brain is similar to that of 5-hydroxytryptamine (3) the most important variable controlling the synthesis of phenylethylamine is the activity of aromatic amino acid decarboxylase (4) p-tyramine is synthesised at about half the rate of phenylethylamine and is thus quantitatively important in metabolic terms.

Adolescent↗
PubMed2001

A tryptamine analog with high affinity to the heart tissues is a potential antiarrhythmic agent.

A novel tryptamine analog, 1-methyl-3-[N-(3-indolyl)ethyl]carbamoyl-1,4-dihydropyridine (T-CDS) was synthesized and converted into a stable, solid complex with 2-hydroxypropyl-beta-cyclodextrin. An aqueous solution of the complex was given intravenously to dogs and the concentration of T-CDS and its corresponding quaternary (T-Q+) forms were monitored in the blood for 50 min. The effect of the drug on vital heart parameters was monitored throughout the studies. At the end of the experiment the dogs were sacrificed and the concentration of the quaternary pyridinium form (T-Q+) was determined in the different heart tissues, as well as in the kidney, liver, lung, brain, urine and cerebrospinal fluid. The compound was found to be selectively bound to the heart muscles and showed different concentrations in different heart tissues. The T-Q+ concentrations were much higher in the heart after administration of the dihydro form (T-CDS), than after administering T-Q+ directly. The compound was found to be active on certain vital signs of the cardiovascular system and could be an effective and safe antiarrhythmic agent.

Animals↗
PubMed1986

Effect of tryptamine on the behavior of mice.

The effects of tryptamine (TRM) on behavior were investigated in mice. TRM at a dose of 50 mg/kg i.p. induced an inhibition of locomotor activity and, at doses ranging from 150 to 300 mg/kg, induced peculiar behaviors such as head twitch, head weaving, forepaw treading, hindlimb abduction and Straub tail. These behavioral effects were continuous, although TRM rapidly disappeared from the brain. Methysergide, a 5-hydroxytryptamine (5-HT) receptor antagonist, completely abolished TRM-induced excitatory behaviors and p-chlorophenylalanine, a 5-HT depleter, significantly inhibited the behaviors. Our results show that TRM induced both the depression and excitation in the behavior of mice depending on the dosage and TRM-induced excitatory behaviors may be attributed to both its direct stimulation of 5-HT receptors and facilitation of 5-HT release.

Animals↗
PubMed1985

Analysis of cheese for histamine, tyramine, tryptamine, histidine, tyrosine, and tryptophane.

A method is described for determining the content of selected biologically active amines (histamine, tyramine, tryptamine) and amino acids (histidine, tyrosine, tryptophane) in cheeses by high performance liquid chromatography. The amines and amino acids were quantified by employing a counter ion-containing mobile phase and by comparing peak areas of high performance liquid chromatography charts for sample cheeses versus standard cheeses containing known amounts of added amines based on dual injections of samples and standards. Recovery of amines and amino acids varied from 87.5 to 111%. Histamine, which has been associated with food poisoning in concentrations of 185 mg/100 g in Swiss cheese and 180 to 500 mg/100 g in fish, was found in concentrations above 500 mg/100 g in Swiss cheese. The high performance liquid chromatography analytical method should be useful for screening to detect cheese samples containing toxic amounts of histamine and for research studies designed to determine the cause and effect relationships for histamine production in cheese.

Cheese↗
PubMed2000

A highly conserved aspartic acid (Asp-155) anchors the terminal amine moiety of tryptamines and is involved in membrane targeting of the 5-HT(2A) serotonin receptor but does not participate in activation via a "salt-bridge disruption" mechanism.

Discovering the molecular and atomic mechanism(s) by which G-protein-coupled receptors (GPCRs) are activated by agonists remains an elusive goal. Recently, studies examining two representative GPCRs (rhodopsin and alpha(1b)-adrenergic receptors) have suggested that the disruption of a putative "salt-bridge" between highly conserved residues in transmembrane (TM) helix III, involving aspartate or glutamate, and helix VII, involving a basic residue, results in receptor activation. We have tested whether this is a general mechanism for GPCR activation by constructing a model of the 5-hydroxytryptamine (5-HT)(2A) receptor and characterizing several mutations at the homologous residues (Asp-155 and Asn-363) of the 5-HT(2A) serotonin receptor. All of the mutants (D155A, D155N, D155E, D155Q, and S363A) resulted in receptors with reduced basal activity; in no case was evidence for constitutive activity revealed. Structure-function studies with tryptamine analogs and various Asp-155 mutants demonstrated that Asp-155 interacts with the terminal, and not indole, amine moiety of 5-HT(2A) agonists. Interestingly, the D155E mutation interfered with the membrane targeting of the 5-HT(2A) receptor, and an inverse relationship was discovered when comparing receptor activation and targeting for a series of Asp-155 mutants. This represents the first known instance in which a charged residue located in a putative TM helix alters the membrane targeting of a GPCR. Thus, for 5-HT(2A) receptors, the TMIII aspartic acid (Asp-155) is involved in anchoring the terminal amine moiety of indole agonists and in membrane targeting and not in receptor activation by salt-bridge disruption.

Animals↗
PubMed1991

A study on the origins of urinary serotonin and tryptamine.

A sensitive gas chromatography/negative ion chemical ionization mass spectrometric (GC/NICIMS) method was devised and by using deuterated L-tryptophan-3,3-d2(Trp-d2) as a tracer, the detailed in vivo metabolism of serotonin (5-HT) and tryptamine (TA) was investigated. A human was administered orally with 10 mg/kg Trp-d2 and rats were injected intra-peritoneally with 50 mg/kg Trp-d2. The ratios of the level of 5-HT-d2 derived from Trp-d2 to that of endogenous 5-HT-d0 and that of TA-d2 to that of TA-d0 were measured in urine and some organs of rats at times up to 4 hr after administration. It is concluded that urinary excretion of 5-HT might reflect its turnover in the central nervous system and that of TA might reflect its peripheral turnover.

Administration, Oral↗
PubMedDate not supplied

[Simultaneous detection of tryptamine and dopamine in the substantia nigra and raphe nuclei in rats using specific antibodies].

Using a double-labelling procedure, morphological relationships existing between dopaminergic and indoleaminergic neuronal systems in rat brain were investigated. Firstly, thanks to a tryptamine (T) antiserum, we visualized this indoleamine in all mesencephalic regions and showed that the T-immunoreactivity (IR) seems to overlap with the staining observed from serotonin (HT) and 5-methoxytryptamine (MT) antisera. Secondly, using a monoclonal anti-dopamine (DA) antibody and our anti-T antibodies, the simultaneous and specific detection of these compounds enabled us to define the chemically relationships existing between the dopaminergic and tryptaminergic neuronal systems from substantia nigra to raphe nuclei. No co-localization exists. But, the intensity of T-IR decreases from the back to the front, whereas the DA-staining decreases in the opposite way, indicating possible interactions at the end of substantia nigra and B9 area.

Animals↗
PubMed1989

Increased serotonin efflux by a partially oxidized serotonin: tryptamine-4,5-dione.

A partially oxidized serotonin (5-HT) was synthesized electrochemically from 5-HT in an acidic solution. This compound was characterized by its chromatographic and electrochemical properties and identified by mass spectroscopy and NMR as tryptamine-4,5-dione (4,5-DKT). In in vitro superfusion experiments, 10(-5)M 4,5-DKT significantly increased the basal 5-HT efflux from both rat hippocampal and striatal fragments. In contrast, 10(-5) M 4,5-DKT did not change the release of dopamine or its metabolite, 3,4-dihydroxyphenylacetic acid from striatal fragments. Continuous perfusion of 4,5-DKT did not modify the effect of KCl on either 5-HT or dopamine release from both brain areas. In in vitro incubation experiments, 10(-8) to 10(-5) M 4,5-DKT evoked 5-HT efflux from rat hippocampus in a dose-dependent fashion. When 10(-4) and 10(-5) M fluoxetine was incubated with 10(-6) M 4,5-DKT, it partially blocked 4,5-DKT-induced 5-HT release. Pargyline, at 10(-5) M inhibited significantly the 5-hydroxyin-doleacetic acid efflux, but did not modify the 4,5-DKT-stimulated 5-HT release. Incubation of 4,5-DKT with glutathione (GSH) and mercaptoethanol indicated that 4,5-DKT binds to sulfhydryl groups. An evidence of GSH-4,5-DKT conjugate was also observed after incubation of 4,5-DKT with a brain homogenate. The interaction of 4,5-DKT with GSH or mercaptoethanol was blocked effectively with N-ethylmaleimide. It is possible that sulfhydryl groups are involved in the mechanism of 4,5-DKT action on 5-HT release.

3,4-Dihydroxyphenylacetic Acid↗