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PubMed1991

Interactions of 5-hydroxytryptamine with oxidative enzymes.

Peroxidase (EC 1.11.1.7)/H2O2, ceruloplasmin (human type X)/O2, and tyrosinase (EC 1.14.18.1)/O2 all oxidized the indolic neurotransmitter 5-hydroxytryptamine (5-HT) in the physiological pH domain. Peroxidase/H2O2 oxidized 5-HT at pH values down to about 2.5. All oxidation reactions generated complex mixtures of products which included at least one known neurotoxin, tryptamine-4,5-dione. In general, the enzymatic oxidation pathways paralleled the in vitro electrochemical oxidation of 5-HT which has permitted suggestions to be made concerning the probable mechanisms of the enzyme-mediated reactions.

Ceruloplasmin↗
PubMed1993

Activity of serotonin (5-HT) receptor agonists, partial agonists and antagonists at cloned human 5-HT1A receptors that are negatively coupled to adenylate cyclase in permanently transfected HeLa cells.

The activity of serotonin (5-HT) receptor agonists, partial agonists and antagonists, and various other neurotransmitter receptor antagonists at human 5-HT1A receptors that are negatively coupled to adenylate cyclase in permanently transfected HeLa cells was investigated. 5-HT1A receptor-mediated inhibition of adenylate cyclase was studied by measuring inhibition of cAMP accumulation, induced by forskolin. At 100 microM forskolin produced a 100-fold increase in cAMP formation: 5-HT concentration dependently inhibited the cAMP formation; maximal inhibition was attained at 1 microM 5-HT and represented 90% of the stimulated cAMP formation. Full inhibition was observed with 5-HT1A receptor agonists: N,N-dipropyl-8-hydroxy-2-aminotetralin (8-OH-DPAT) and flesinoxan, and non-selective 5-HT receptor agonists: d-lysergic acid diethylamide (d-LSD), RU 24,969, bufotenine, methysergide and tryptamine. The rank order of potency of the compounds for inhibiting the cAMP formation corresponded to the rank order of the binding affinities of the drugs for the 5-HT1A receptor. Partial inhibition was obtained with submicromolar concentrations of buspirone, spiroxatrine and ipsapirone. A slight inhibition was observed with 1 microM 5-HT receptor agonist CP 93129 and 1 microM 5-HT receptor antagonists mesulergine and BW-501. No inhibition was found with: the 5-HT receptor agonists quipazine, sumatriptan and 1-(2,5-dimethoxy-4-methylphenyl)-2- aminopropane (DOM); the 5-HT receptor antagonist ICS-205,930; and other neurotransmitter receptor antagonists such as pindolol, CGP 20712-A, prazosin, sulpiride and pyrilamine. Spiperone and pindolol fully antagonized the agonist-mediated inhibition of forskolin-stimulated cAMP formation. Partial inhibition of the agonist-mediated inhibition of forskolin-stimulated cAMP formation was apparent with 1 microM ocaperidone and 1 microM ipsapirone. It can be concluded that HeLa cells, permanently expressing human 5-HT1A receptors, are a valid cellular system for studying the negative coupling of 5-HT1A receptors to adenylate cyclase and the action of compounds thereupon.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1993

Identification of 5-hydroxytryptamine1D binding sites in sheep caudate nucleus membranes.

Radioligand binding measurements were performed in membranes of sheep caudate nucleus using [3H]5-hydroxytryptamine (5-HT). [3H]5-HT labeled a population of high affinity binding sites with a Kd of 1.9 +/- 0.1 nM and a Bmax of 19.8 +/- 2.2 fmol/mg tissue. Combined 5-HTID/E binding sites were the predominant 5-HT1 subtype, accounting for 78% of the total population of 5-HT1 binding sites. 5-Carboxamidotryptamine (5-CT) and sumatriptan yielded inhibition curves which best fitted a two-site model with high affinity values of 0.8 and 10.1 nM, and 1000 and 206 nM for their low affinity components. The proportion of the high affinity 5-CT and sumatriptan binding sites was 79 and 72%. The binding affinity profile of 5-HT1D binding sites [5-CT > 5-HT > d-LSD > 5-MeOT > sumatriptan > RU 24,969 > metergoline > tryptamine = rauwolscine = methylsergide > yohimbine = methiothepin > TFMPP = 8-OH-DPAT > 2-methyl-5-HT > mCPP = quipazine = CP 93,129 > ketanserin > (-)-propranolol = haloperidol = ipsapirone] compares well to that reported for 5-HT1D receptor sites in human caudate and cortex (correlation coefficient: 0.99 and 0.98). The present results indicate that sheep caudate nucleus is a valid tissue for studying interaction of compounds with 5-HT1D binding sites in the relative absence of 5-HT1E binding sites.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1995

Differentiation between partial and silent 5-HT1D beta receptor antagonists using rat C6-glial and Chinese hamster ovary cell lines permanently transfected with a cloned human 5-HT1D beta receptor gene.

Intrinsic activities of serotonin (5-HT) receptor ligands at cloned human 5-HT1D beta receptor sites were determined by measuring cAMP responses in two permanently transfected cell types: rat C6-glial and Chinese hamster ovary (CHO)-K1 cells. Both transfected cell lines expressed a similar 5-HT1D beta receptor density (361 to 448 fmol/mg protein) and displayed a number of similar cAMP responses: marked inhibition of forskolin-stimulated cAMP formation by 5-HT; a similar agonist potency and efficacy with 5-carboxamidotryptamine (5-CT), 5-methoxytryptamine, bufotenine, sumatriptan, 7-trifluoromethyl-4(4-methyl-1-piperazinyl)-pyrolo-(1,2-a)quinoxal ine (CGS 12066B), 5-methoxy-3(1,2,3,6-tetrahydro-4-pyridinyl)1H-indole (RU 24,969), and tryptamine, their maximal effect being comparable to that of 5-HT; less agonist efficacy with m-trifluoro-phenyl-piperazine (TFMPP) (it inhibited at most 63% of stimulated cAMP formation); and antagonist activity against the 5-CT-mediated agonist response with methiothepin, 2'-methyl-4-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid [4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide (GR 127,935), and ritanserin. Metergoline and 1-naphtylpiperazine showed different intrinsic activities. In contrast to their pronounced antagonist activity in the transfected CHO-K1 cell line, the antagonist effect was only partial and absent for metergoline and 1-naphtylpiperazine in the transfected C6-glial cell line, respectively. In conclusion, these cell lines are useful as a tool to measure with high sensitivity differences in intrinsic activities of 5-HT receptor ligands and, therefore, discriminate between silent antagonists (no intrinsic activity) and antagonists with intrinsic activity (i.e. partial agonists), even though this intrinsic activity may be relatively weak.

Animals↗
PubMed1976

Evidence for the existence of a raphe projection to the substantia nigra in rat.

The effect of electrical stimulation of the median raphe nucleus on the activity of spontaneously firing single neurones in the substantia nigra and mesencephalic reticular formation (MRF) has been investigated in urethane anaesthetized rats. Depression of activity was the predominant effect observed although this was sometimes accompanied by periods of excitation. Some neurones were only excited. The latency of inhibition of substantia nigra neurones was constant whereas that of MRF neurones was more variable. Microiontophoretically applied 5-hydroxy-tryptamine (5-HT) and dopamine (DA) produced mainly inhibition of neuronal activity, but excitation and biphasic effects were also seen. There was a good correlation between the direction of neuronal responses in the substantia nigra to median raphe stimulation and to the effects of 5-HT but not DA. Discrete electrolytic lesions of the median raphe nucleus were followed by a decrease in 5-HT but not GABA concentrations in the substantia nigra. In addition striatal 5-HT, GABA and NA concentrations were unchanged whereas striatal DA was increased. These observations strongly suggest that the substantia nigra receives a direct inhibitory input from the median raphe nucleus and this pathway uses a 5-HT-like neurotransmitter. This pathway probably contributes to the regulation of nigrostriatal dopaminergic transmission.

Animals↗
PubMed1978

Transmitter histochemistry of the rat olfactory bulb. II. Fluorescence histochemical, autoradiographic and electron microscopic localization of monoamines.

The rat olfactory bulb was studied with the Falck-Hillarp formaldehyde fluorescence technique, including recent modifications, autoradiography and electron microscopic cytochemistry (permanganate fixation). Some periglomerular cells and few superficial tufted cells take up and accumulate catecholamines and precursors. They probably represent dopamine cells. In the glomeruli, probable 5-hydroxy-tryptamine nerve terminals could be identified. In the granular and external plexiform layers, noradrenaline axon terminals were present. At the ultrastructural level, monoamine boutons were in synaptic contact with dendritic spines of granule cells and in the glomeruli, probable 5-hydroxytryptamine boutons formed synapses with periglomerular cell dendrites. Therefore, monoamine afferents to the bulb may exert their influence via interneurons.

Animals↗
PubMed1980

Increased sensitivity to intracerebroventricular infusion of serotonin and deaminated indoles after lesioning rat with dihydroxytryptamine.

Rats were prepared with a chronic intracerebroventricular cannula, and treated with intracisternal 5,7-dihydroxytryptamine (DHT) after i.p. desmethylimipramine or control vehicle. After recovery, they were tested behaviorally by direct observation and electronic monitoring of motor activity. Intraventricular infusion of a placebo or 5-hydroxyindoleacetic acid (5-HIAA) had little effect, but serotonin (5-HT) decreased, and norepinephrine increased locomotor activity in intact rats. Following pretreatment with 5,7-DHT, a small increase in locomotor activity was noted which was not altered by intracranial infusion of vehicle. In contrast, infusions of 5-HT produced a striking dose-dependent (ED50 = 5 micrograms/min) pattern of hyperactivity, 'myoclonic' jerking movements, postural changes, and autonomic responses. Norepinephrine increased locomotor activity in the DHT-lesioned rats (but not significantly more than in controls), but failed to produce the myoclonic syndrome. The deaminated indoles, indoleacetaldehyde and 5-HIAA were more potent than 5-HT in producing the myoclonic response; tryptamine when infused at an equimolar dose had no effect. The putative serotonin antagonists, cyproheptadine and methiothepin (i.p.), were more effective in blocking responses to infused 5-HT than to equipotent doses of deaminated indoles. These behavioral responses may represent exaggerated ex"itatory effects mediated by serotonin in the brain stem and spinal cord, possibly modified by altered forebrain mechanisms. A neurophysiologic or neuropharmacologic role for deminated indoles should be reconsidered as they may not merely be inactive metabolites.

5,7-Dihydroxytryptamine↗
PubMed1980

Monoaminergic denervation of the rat hippocampus: microiontophoretic studies on pre- and postsynaptic supersensitivity to norepinephrine and serotonin.

The responsiveness of hippocampal CA3 pyramidal neurons to microiontophoretic applications of serotonin (5-HT), norepinephrine (NE), gamma-aminobutyric acid (GABA) and isoproterenol (ISO) was assessed in rats following 5,7-dihydroxy-tryptamine (5,7-DHT) and 6-hydroxydopamine (6-OHDA) pretreatments and bilateral locus coeruleus lesions. The intraventricular administration of 200 micrograms (free base) of 5,7-DHT and of 6-OHDA produced 89% and 93% decreases of 5-HT and NE respectively. None of these pretreatments modified the inital responsiveness to, or recovery from iontophoretic application of 5-HT. In 6-OHDA pretreated and locus-lesioned rats, the initial effectiveness of NE was not altered but its effect was markedly prolonged. However, there was no such prolongation of the effect of ISO which is not a substrate for the high affinity NE reuptake. The effect of GABA was not affected by these pretreatments. Acute pharmacological blockade of the NE reuptake with desipramine (5 mg/kg, i.p.) similarly induced a prolongation of the effect of iontophoretically applied NE, while fluoxetine (10 mg/kg, i.p.) a 5-HT reuptake blocker, failed to alter the recovery of pyramidal cells from iontophoretic application of 5-HT. It is concluded that 5-HT denervation induces neither pre- nor postsynaptic types of supersensitivity in hippocampal pyramidal cells, contrasting with the previously shown supersensitivity of ventral lateral geniculate and amygdaloid neurons following 5-HT denervation. NE denervation fails to induce a postsynaptic type of supersensitivity but leads to a marked prolongation of the response to NE indicative of a presynaptic mechanism. These results underscore the necessity for regional studies of neurotransmitters and drug action.

Animals↗
PubMed1982

Effect of 5-HT depletion of the hippocampus on neuronal transmission from perforant path through dentate gyrus.

Stimulation of the perforant pathway (pp) elicits a characteristic evoked action potential (EAP) in the granule cell layer of the dentate gyrus. The EAP was recorded in rats depleted of hippocampal serotonin (5-HT) by prior injection of p-chloroamphetamine (PCA) or 5,7-dihydroxy-tryptamine (5,7-DHT) as well as in untreated animals during two behavioral states, slow-wave sleep (SWS) and still-alert behavior (SAL). As reported previously, in untreated rats the amplitude of the EAP response was significantly greater during SWS than SAL. Stimulation of the median raphe nucleus (MR) prior to stimulating the pp (prestimulation) augmented the EAP response, but only during SWS. In contrast, in animals injected with PCA or 5,7-DHT there was no difference of the amplitude of the EAP during SWS and SAL. However, the augmentation of the EAP during SWS produced by prestimulation of the median raphe was still present. It is concluded that 5-HT innervation of the dentate gyrus may be involved in the behavioral modulation of the EAP response. Modulation of the EAP following prestimulation of the MR appears to be effected by a non-serotonergic input to the dentate gyrus originating in, or coursing through, the median raphe.

5,7-Dihydroxytryptamine↗
PubMed1984

Enteric receptors for 5-hydroxytryptamine.

[3H]5-hydroxytryptamine [( 3H]5-HT) was used as a radioligand to study enteric 5-HT receptors. Membranes were derived from preparations of longitudinal muscle with adherent myenteric plexus and of mucosa-submucosa dissected from guinea pig and rabbit small intestines. Filtration and radioautographic analyses were used. Specific [3H]5-HT binding was found in both preparations. Binding was saturable and dissociable with equilibrium dissociation constants (Kd) of 2.7 and 1.4 nM, respectively. A kinetic estimate of Kd (1.5 nM) was similar to that determined by saturation analysis and the Hill coefficient approximated unity. Ring-hydroxylation of indoles was found to be a requirement for antagonism of [3H]5-HT binding. On the other hand, substitutions could be made in the aliphatic side chain of tryptamines without destroying the affinity of analogues for the binding sites. The inability of antagonists to displace [3H]5-HT indicated that the binding sites were not muscarinic or nicotinic receptors, alpha- or beta-adrenoceptors, H1 or H2 histamine receptors, dopamine receptors or either the S1 or S2 types of 5-HT receptor that have been found in the brain. Frozen section dry-mount radioautography revealed the [3H]5-HT binding sites to be located in ganglia of the myenteric plexus and at the boundary between the mucosa and submucosa. The similarity between the structure-activity requirements for affinity at the [3H]5-HT binding sites and activation of neural or M receptors for 5-HT in the gut, as well as the characteristics and location of the binding sites suggests that they are enteric neural receptors for 5-HT.

Animals↗
PubMed1985

Pharmacological characterization of solubilized 5-HT1 serotonin binding sites from bovine brain.

This report describes the pharmacologic characterization of [3H]serotonin binding activity solubilized from bovine frontal cortical membranes. The ability of a number of serotonin (5-HT) and lysergic acid diethylamide (LSD) analogs to compete with [3H]serotonin and D-[3H]LSD for binding to membrane and solubilized 5-HT1 sites has been investigated. The results indicate that the solubilized binding site is probably of the 5-HT1B type. Fifteen of the 21 compounds tested exhibit nearly identical affinity for membrane or solubilized 5-HT1 binding sites. However, some important differences were observed, and these may help elucidate the molecular structure of the binding site. In particular, some N-substituted tryptamine analogs show a markedly lower affinity for solubilized 5-HT1 sites compared to their binding to intact membranes. Further, the solubilized site does not distinguish stereoisomers of LSD: both D- and L-LSD bind to solubilized 5-HT1 sites with comparable high affinities, whereas D-LSD has a markedly higher affinity for the membrane 5-HT1 site. Methiothepin, which binds to the 5-HT1 site primarily through its amine groups, has virtually no affinity for the solubilized receptor, whereas it is quite potent at competing for [3H]serotonin binding to membrane sites. These observations lead to the conclusions that in bovine cortical membranes, the 5-HT1 site contains both indole and amine attachment sites. After solubilization, the indole attachment site retains its binding properties, but the amine attachment site has been significantly altered.(ABSTRACT TRUNCATED AT 250 WORDS)

Amines↗
PubMed1986

Studies on serotonin-accumulating cells in rabbit retinal cultures.

The serotonin-accumulating neurones in rabbit retinal cultures were studied, using immunohistochemistry to localize serotonin. Double-labelling experiments showed that serotonin-accumulating cells in culture and intact retinas react positively to antiserum PGP 9.5, which is neurone-specific. The uptake process of serotonin is very specific; known serotonergic blockers, such as chlorimipramine, abolished transport, while benztropine, a dopamine uptake blocker, was ineffectual. Analogues of serotonin such as tryptamine, tryptophan and 5-hydroxytryptophan at concentrations 100-fold those of exogenous serotonin did not appear to compete with the transport of the amine. Newly dissociated retinal cells from 1-5-day postnatal rabbits which lack processes have the capacity to take up exogenous serotonin; these cells when kept in culture grew processes and appeared to reach maximum development after 6-15 days. Dissociated retinal cells subjected to density centrifugation resulted in the production of an enriched (4-fold) population of serotonin-accumulating cells. Since most of the endogenous serotonin was associated with this fraction, it is concluded that the serotonin-accumulating cells contain serotonin.

Animals↗
PubMed1987

First characterization of 5-hydroxytryptophan in rat brain by using specific antibodies.

DL-5-Hydroxytryptophan (5-HTP) was conjugated to bovine serum albumin and human serum albumin with glutaraldehyde (G). These conjugates made it possible to raise specific antisera in two rabbits. Their specificity and affinity were evaluated using an enzyme-linked immunosorbent assay and immunocytochemistry. For two antisera obtained, the most immunoreactive antigen was 5-HTP-G-protein, indicating that the same immune response was developed. The other conjugated indoleamines (5-methoxytryptophan-G-protein, tryptophan-G-protein) were poorly recognized or not at all (5-methoxytryptamine-G-protein, serotonin-G-protein, tryptamine-G-protein). These 5-HTP antisera enabled us to specifically visualize the precursor of serotonin in the raphe nuclei of G-fixed rat brains.

5-Hydroxytryptophan↗
PubMed1988

The presence of tyramine and related monoamines in the nerve cord and some other tissues of the lobster, Homarus americanus.

This report shows the existence of endogenous p-tyramine in the nerve cord and some organs of the lobster. Their concentrations are lower than those of dopamine or 5-hydroxytryptamine. The nerve cord levels of m-tyramine, beta-phenylethylamine and tryptamine are much lower than those of the phenolic or catecholic amines. The finding that the administration of an aromatic-L-amino acid decarboxylase inhibitor leads to a decrease of p-tyramine gives further evidence that this amine is synthesized from p-tyrosine, which is also found in high concentrations in the lobster nerve cord. The widespread distribution of p-tyramine in the nervous system and peripheral tissues of the lobster suggests that this amine may have additional roles rather than functioning only as a precursor of p-octopamine.

Animals↗
PubMed1990

5-HT1 receptor binding sites in the guinea pig superior colliculus are predominantly of the 5-HT1D class and are presynaptically located on primary retinal afferents.

The superficial layers of the guinea pig superior colliculus are characterized by high densities of [3H]5-HT binding sites. We have chosen receptor autoradiography to establish the drug binding profile and the localization of these sites. The binding of [3H]5-HT to guinea pig superior colliculus was nearly completely blocked by drugs such as 5-carboxamido-tryptamine and yohimbine, but only slightly sensitive to the 5-HT1 receptor agonist 8-hydroxy-dipropylamino-tetralin. 5-HT1C antagonists such as mesulergine or the beta-adrenergic receptor blocking compound SDZ 21-009 did not show any effect. The profile of the majority of these sites corresponds to that of 5-HT1D sites. Unilateral enucleation resulted in a nearly complete depletion of [3H]5-HT binding in the contralateral superior colliculus, whereas [125I]Bolton-Hunter-8-methoxy-N-propylaminotetralin binding sites, corresponding to 5-HT1A receptors, were preserved. These results indicate that 5-HT1D (and not 5-HT1A) receptors might be presynaptically localized on non-serotoninergic neuronal pathways. The guinea pig visual system may be a useful model for the study of the properties of these presynaptic 5-HT heteroreceptors.

Afferent Pathways↗
PubMed1992

Further evidence for differential affinity states of the serotonin1A receptor in rat hippocampus.

The binding profile of [3H]8-hydroxy-2-(di-N-propylamino)-tetralin ([3H]8-OH-DPAT) to serotonin1A (5-HT1A) sites in rat hippocampal, frontocortical and striatal membranes has been compared. In these regions, [3H]8-OH-DPAT labels both a high and a low-affinity binding site; the affinity values for each of the two sites are comparable in the different brain regions, but have different maximal capacity. By modifying the experimental conditions in a series of hippocampal membrane preparations, reciprocal changes in the proportion of the two sites were observed suggesting that they represent, at least in this region, different conformations or affinity states of a single receptor protein. In contrast to the lower affinity state, it appears that the high-affinity state is stabilized by coupling with a G-protein. Evidence supporting this statement is provided by addition of the guanine nucleotide Gpp(NH)p, breakage of labile disulfide bonds using N-ethylmaleimide and increasing membrane rigidity with ascorbate-induced lipid peroxidation, conditions which all reduced the density of receptors in the high-affinity state. Moreover, the high-affinity state appears to be stabilized at the expense of the lower affinity state in the presence of Mn2+. On the other hand, a complete shift to the low-affinity binding state was observed after a 24 h in vivo treatment with inhibitors of monoamine oxidase A (phenelzine or clorgyline) but not of monoamine oxidase B (deprenyl). This disappearance of the high-affinity state with a concomitant increase in the binding capacity of the low-affinity state was reproduced by inhibiting monoamine oxidase A in vitro, as well as by reducing preincubation washout periods. Also, competitors of the [3H]8-OH-DPAT binding site, such as serotonin and unlabelled 8-OH-DPAT, display two affinity states while others like (+/-)-propranolol, tryptamine and spiperone recognize a single affinity component. These results suggest that the 5-HT1A binding site may exhibit at least two different affinity states depending upon its microenvironment and the intrinsic activity of the ligand used.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1993

High D-glucose concentrations increase GABA release but inhibit release of norepinephrine and 5-hydroxytryptamine in rat cerebral cortex.

The effect of high D-glucose concentrations on the K+ (15-25 mM)-evoked release of [3H]GABA, [3H]norepinephrine ([3H]NE), [3H]5-hydroxy- tryptamine ([3H]5-HT) and [3H]acetylcholine ([3H]ACh) was investigated in rat cerebral cortical slices and synaptosomes superfused with Krebs' solution which normally contains 11.1 mM glucose. In slices, the release of [3H]GABA was enhanced by increasing D-glucose by 32-320 mM, the release of [3H]NE and [3H]5-HT was inhibited when D-glucose was increased by 60-320 mM but the release of [3H]ACh was not affected. The increase of [3H]GABA release and the inhibition of [3H]NE release were mimicked by D-fructose and NaCl at similar osmolarities, whereas dimethylsulfoxide (DMSO; a freely membrane-permeable drug) at equimolar concentrations failed to affect the release of [3H]GABA and [3H]NE. The GABAB receptor antagonist p-(3-aminopropyl)-p-diethoxymethyl- phosphinic acid (CGP 35348) abolished the inhibitory effect of an increase in D-glucose by 60 and 100 mM on [3H]NE release but only tended to diminish the inhibition caused by an increase by 320 mM. In synaptosomes, the K(+)-evoked release of 3H-GABA was enhanced by increasing D-glucose by 60-320 mM. The K(+)-evoked release of [3H]NE was only inhibited when D-glucose was increased by 320 mM, whereas it was not affected by an increase by 100 mM. In conclusion, high D-glucose differentially influences neurotransmitter release in the brain cortex. Hyperosmolarity in the extracellular fluid together with an osmotic gradient extra- versus intracellular probably plays a role in the mechanism(s) underlying the changes observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Structural studies of condensation products of biogenic amines as inhibitors of tryptophan hydroxylase.

The effects of condensation products of dopamine and indoleamines on the activity of tryptophan hydroxylase (TPH) were evaluated to determine the structures associated with modulation of this enzyme activity. The compounds having a catechol structure, such as 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, markedly inhibited the activity of the enzyme prepared from the rat brain. The inhibition was non-competitive in terms of both the biopterin cofactor and the substrate L-tryptophan. Substitution on the one or two positions of catechol isoquinolines did not affect the inhibitory activity towards TPH. Among these compounds, a charged substance, 1,2[N]-dimethyl-6,7-dihydroxy-isoquinolinium ion, was an extremely potent inhibitor; the Ki values were 0.88 +/- 0.17 and 0.64 +/- 0.08 microM (mean +/- S.D.) in terms of the substrate and cofactor, respectively. By contrast, the condensation products of tryptophan and tryptamine with acetaldehyde scarcely affected TPH activities. 1-Methyl-1,2,3,4-tetrahydroisoquinoline, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium ion (MPP+) were almost inactive. These results indicated that the catechol structure recognized and combined with TPH at a binding site different from that of the substrate or cofactor and the positive charge on the dopamine-derived substance enhanced the affinity to TPH. The selective inhibition of TPH by dopamine-derived catechol isoquinolines was discussed in relationship to the interactions between catecholamines, indoleamines and their metabolites in the brain under physiological and pathological conditions.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗