Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prompted by previous findings that a p-dimethoxy substitution pattern on an aromatic ring permits retention of dopaminergic agonist effects in certain ring systems, catechol derivatives of which are potent dopaminergic agonists, an 8,11-dimethoxy substitution pattern was introduced into the aporphine ring in place of the 10,11-dihydroxy moiety in apomorphine. Acid-catalyzed rearrangement of an appropriate morphine derivative provided the aporphine ring system with retention of the stereochemical integrity of the 6a asymmetric center. The hydroxyl group at position 10 was removed by catalytic hydrogenolysis of its phenyltetrazoyl ether. The methyl ether of the resulting 11-hydroxyaporphine was iodinated in high yield at position 8 with trifluoroacetyl hypiodite. This is the first account of synthesis of an iodinated aporphine derivative. The 8-iodo substituent was replaced with methoxyl by reaction with sodium methoxide and cuprous iodide. Neither the N-methyl target compound 7 nor the N-n-propyl derivative 8 demonstrated dopaminergic nor serotonergic agonism. However, 7 exhibited receptor-binding characteristics and other pharmacological properties suggesting that it may be a 5-HT1A receptor antagonist.
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PMID:5-HT1A-receptor antagonism: N-alkyl derivatives of (R)-(-)-8,11-dimethoxynoraporphine. 256 41

Serotonin is a well-known neurotransmitter and neuroimmunomodulator which has been reported to modulate T cell and NK cell proliferation. In this study we investigated whether serotonin could regulate mitogen-stimulated proliferation of the mature B lymphocyte. Mouse and rat spleen cells were cultured with serotonin in the presence or absence of a combination of Escherichia coli lipopolysaccharide and dextran sulfate, and proliferation was assessed by [3H]thymidine uptake or propidium iodide staining of DNA. Serotonin alone had no effect on spleen cell proliferation, while it increased mitogen-stimulated B cell proliferation in a dose- and time-dependent manner. These effects were reproduced by the selective 5-HT1A receptor agonist 8-OH-DPAT. Serotonin- or 8-OH-DPAT-induced increase in proliferation could be blocked by the 5-HT1A receptor antagonists (+)WAY 100135 and propranolol. Moreover, lipopolysaccharide-activated mouse spleen cells expressed specific binding sites for [3H]8-OH-DPAT. These results show that serotonin upregulates mitogen-stimulated B lymphocyte proliferation through 5-HT1A receptors, thus providing an important link between this neurotransmitter and the immune system.
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PMID:Serotonin upregulates mitogen-stimulated B lymphocyte proliferation through 5-HT1A receptors. 775 18

The role of brain amines, possibly involved in psychological stress, was evaluated and we postulate that the 5-hydroxytryptamine 5-HT3 receptors in the central nervous system are involved in the gastric lesion formation by psychological stress. The stress was in a communication box paradigm, in which each nonshocked mouse (responder) was placed in a Plexiglas compartment adjacent to mice receiving electrical shocks (sender). The responder mice revealed rather depressed gastric secretion, but developed gastric lesions which are significantly attenuated by pretreatment of dl-p-chlorophenylalanine methyl ester:HCl (PCPA; 200-400 mg/kg p.o.), but not 6-hydroxydopamine (6-OH-DA; 60 micrograms/body i.c.v. or 80 mg/kg i.p. 1 hr after a 20-mg/kg i.p. dose of desipramine). Oral treatment with GR38032F (0.01-1 mg/kg), ICS205-930 (0.01-20 mg/kg), MDL72222 (0.01-1 mg/kg), metoclopramide (0.1-100 mg/kg), ketanserin (0.01-10 mg/kg) and sulpiride (32-320 mg/kg) dose-dependently attenuated the psychological stress lesion formation, and the activity was arranged in the order of their in vitro binding affinities for the 5-HT3, but not 5-HT1A or 5-HT2 receptors. In contrast, a peripherally acting 5-HT3 antagonist, M-840 ([[3-(1-methyl-1H-indol-3-yl)-1,2,4-oxadiazol-5- yl]-methyl]trimethyl-ammonium iodide), dopamine acting compounds, haloperidol and FR64822 [N-(4-pyridylcarbamoyl)amino-1,2,3,6- tetrahydropyridine), and antisecretory drugs, atropine and famotidine, minimally affected the lesion formation.
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PMID:A mechanism of 5-HT3 receptor mediation is involved etiologically in the psychological stress lesion the stomach of the mouse. 796 2

In order to develop tracers with higher specific activity to supplant the currently used [3H]-8-OH-DPAT [8-hydroxy-2-(N,N-di-n-propylamino)tetralin] for in vitro and in vivo evaluation of 5-HT1A receptors, a new radioiodinated ligand was prepared. (R,S)-trans-8- Hydroxy-2-[N-n-propyl-N-(3'-iodo-2'-propenyl)amino]tetralin (trans-8-OH-PIPAT), 8, was synthesized by a 10-step reaction. Binding studies with rat hippocampal membrane homogenates showed that 8 exhibited a Ki value of 0.92 nM against (R,S)-[3H]-8-OH-DPAT. Radiolabeled [125I]-8 was prepared from the corresponding tri-n-butyltin precursor via an oxidative iododestannylation reaction with sodium [125I]iodide. Binding studies in the hippocampal homogenates revealed that [125I]-8 bound to a single high-affinity site (Kd = 0.38 +/- 0.03 nM,Bmax = 310 +/- 20 fmol/mg of protein). Competition binding experiments clearly indicated that the new ligand displayed the expected 5-HT1A receptor binding profile. The rank order of potency was (R,S)-trans-8-OH-PIPAT > (R,S)- 8-OH-DPAT > WB4101 > 5-HT > (R,S)-trans-7-OH-PIPAT > (R,S)-7-OH-DPAT > (R,S)-propranolol > spiperone >> ketanserin >> dopamine > atropine. This new ligand offers several unique advantages, including high specific activity, high binding affinity, and low nonspecific binding, all of which make it an excellent probe for the investigation and characterization of 5-HT1A receptors.
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PMID:Synthesis of (R,S)-trans-8-hydroxy-2-[N-n-propyl-N-(3'-iodo-2'-propenyl)amino]tetral in (trans-8-OH-PIPAT): a new 5-HT1A receptor ligand. 823 Jan 2

The study was aimed at investigating the repercussions of deficiency in thyroid function with and without thyroid hormone (TH) replacement on the neurochemical entities which underly serotonin (5-HT) neutrotransmission, namely 5-HT1A, 5-HT2A receptors, 5-HT transporter and tryptophan hydroxylase (TPH) in the mature brain. Surgically thyroidectomized male Wistar rats received: (1) an iodine-free diet to produce severe hypothyroidism; (2) hormonal replacement with 15 microgram/kg/day of thyroxine (T4) for 21 days to normalize serum TH levels, or (3) hormonal replacement with 200 microgram/kg/day of T4 for 14 days to produce an excess of circulating THs. Sham-operated rats were used as controls. Neither hypothyroidism nor an excess in serum TH levels affected 3H-8-OH-DPAT binding to 5-HT1A receptors, 3H-citalopram binding to 5-HT transporter and TPH activity in various brain structures indicating that, in the mature brain, the presynaptic entities of 5-HT neurotransmission are resistant to large variations in TH levels. By contrast, hypothyroid rats had a significant decrease in Bmax of 3H-ketanserin binding to cortical 5-HT2A receptors compared to controls. Cortical 3H-ketanserin binding in thyroidectomized rats was normalized after replacement with low-dose T4. Excess serum TH levels in thyroidectomized rats did not produce any changes in cortical 5-HT2A receptors when compared to thyroidectomized rats with normalized TH levels. The present data suggest that the decrease in cortical 5-HT2A receptors is the main neurochemical event underlying the impairing effect of hypothyroidism on 5-HT neurotransmission.
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PMID:Effects of experimental hypothyroidism on 5-HT1A, 5-HT2A receptors, 5-HT uptake sites and tryptophan hydroxylase activity in mature rat brain1. 1036 98

Effects of thyroid hormone deficiency on 5-HT1A receptors, 5-HT2A receptors and serotonin transporter in the brain were studied in thyroidectomised Wistar rats receiving an iodine-free diet and receiving 15 micrograms/kg of thyroxine for 21 days. Binding of 3H-8-OH-DPAT to 5-HT1A receptors and 3H-cytalopram to serotonin transporter were unchanged in hypothyroid rats as compared to the control. 3H-ketanserin binding to 5-HT2A receptors was significantly decreased in the frontal cortex in hypothyroid rats. The cortical 3H-ketanserin binding in thyroidectomised rats was normalised after thyroxine replacement. The data suggest that the decrease in the cortical 5-HT2A receptors is the main consequence of impairing effect of hypothyroidism on serotonin neurotransmission.
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PMID:[Effect of hypothyroidism on 5-HT1A-, 5-HT2A-receptors and serotonin transporter in the rat brain]. 1080 28

The 5-HT1A subtype of receptors for the neurotransmitter serotonin is predominantly located in the limbic forebrain and is involved in the modulation of emotion and the function of the hypothalamus. Since 5-HT1A receptors are implicated in the pathogenesis of anxiety, depression, hallucinogenic behaviour, motion sickness and eating disorders, they are an important target for drug therapy. Here, we review the radioligands which are available for visualisation and quantification of this important neuroreceptor in the human brain, using positron emission tomography (PET) or single-photon emission tomography (SPET). More than 20 compounds have been labelled with carbon-11 (half-life 20 min), fluorine-18 (half-life 109.8 min) or iodine-123 (half-life 13.2 h): structural analogues of the agonist, 8-OH-DPAT, structural analogues of the antagonist, WAY 100635, and apomorphines. The most successful radioligands thus far are [carbonyl-11C] WAY-100635 (WAY), [carbonyl-11C]desmethyl-WAY-100635 (DWAY), p-[18F]MPPF and [11C]robalzotan (NAD-299). The high-affinity ligands WAY and DWAY produce excellent images of 5-HT1A receptor distribution in the brain (even the raphe nuclei are visualised), but they cannot be distributed to remote facilities and they probably cannot be used to measure changes in endogenous serotonin. Binding of the moderate-affinity ligands MPPF and NAD-299 may be more sensitive to serotonin competition and MPPF can be distributed to PET centres within a flying distance of a few hours. Future research should be directed towards: (a) improvement of the metabolic stability in primates; (b) development of a fluorinated radioligand which can be produced in large quantities and (c) production of a radioiodinated or technetium-labelled ligand for SPET.
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PMID:Visualisation of serotonin-1A (5-HT1A) receptors in the central nervous system. 1120 45

1-[2-(4-Methoxyphenyl)phenyl]piperazine (4) is a potent serotonin 5-HT7 receptor antagonist (Ki=2.6nM) with a low binding affinity for the 5-HT1A receptor (Ki=476nM). As a potential positron emission tomography (PET) radiotracer for the 5-HT7 receptor, [(11)C]4 was synthesized at high radiochemical yield and specific activity, by O-[(11)C]methylation of 2'-(piperazin-1-yl)-[1,1'-biphenyl]-4-ol (6) with [(11)C]methyl iodide. Autoradiography revealed that [(11)C]4 showed in vitro specific binding with 5-HT7 in the rat brain regions, such as the thalamus which is a region with high 5-HT7 expression. Metabolite analysis indicated that intact [(11)C]4 in the brain exceeded 90% of the radioactive components at 15min after the radiotracer injection, although two radiolabeled metabolites were found in the rat plasma. The PET study of rats showed moderated uptake of [(11)C]4 in the brain (1.2SUV), but no significant regional difference in radioactivity in the brain. Pretreatment with 5-HT7-selective antagonist SB269970 (3) did not decrease the uptake of [(11)C]4 in the rat brain. Further studies are warranted that focus on the development of PET ligand candidates with higher binding affinity for 5-HT7 and higher in vivo stability in brain than 4.
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PMID:Synthesis and evaluation of 1-[2-(4-[(11)C]methoxyphenyl)phenyl]piperazine for imaging of the serotonin 5-HT7 receptor in the rat brain. 2383 Jun 97