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Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of N-[2-[(substituted chroman-8-yl)oxy]ethyl]-4-(4-methoxyphenyl)butylamines was prepared and examined for their 5-HT1A receptor antagonist activity. The parent compound 3a and seven analogs bearing five kinds of substituents on the chroman ring were prepared from the corresponding 8-hydroxychroman intermediates. Radioligand binding assays proved the compounds 3a-h to have high affinity for the rat hippocampal 5-HT1A receptor with varied selectivity for adrenaline alpha1 and dopamine D2 receptors. Their antagonism was evaluated in a forskolin-stimulated adenylate cyclase assay performed with CHO cells expressing the human 5-HT1A receptor. Among the series, the C6-fluoro analog 3c showed both extremely potent affinity (Ki = 0.22 nM) and antagonism (EC50 = 13 nM) for the 5-HT1A receptor. Correlation analysis using substituent descriptors revealed a linear and negative correlation between molar refractivity of the C6-substituent and the binding affinity expressed in pKi.
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PMID:N-[2-[(substituted chroman-8-yl)oxy]ethyl]-4-(4-methoxyphenyl)butylamines: synthesis and wide range of antagonism at the human 5-HT1A receptor. 911 Dec 99

Inhibition of forskolin-stimulated cyclic AMP accumulation was measured in two stable HeLa cell lines HA6 and HA7 expressing different levels of recombinant human 5-HT1A receptors. These cells were studied previously to characterize another second messenger system activated by 5-HT1A receptors, i.e. calcium mobilization. The pharmacological characterization of the inhibition of cyclic AMP accumulation was made using agonists (5-HT, 8-OH-DPAT, buspirone, MDL 73005) and putative antagonists (SDZ 216-525, NAN-190, WAY-100135, pindolol, propranolol, WAY 100635). It is shown that 5-HT, 8-OH-DPAT, buspirone, MDL 73005 behaved as full (or nearly full) and potent agonists, whereas SDZ 216-525, NAN-190 and WAY-100135 displayed a limited (and similar) degree of intrinsic activity at human 5-HT1A receptors; on the other hand pindolol, propranolol and WAY 100635 behaved as "silent" antagonists. The effects were quantitatively and qualitatively very similar in both cells lines for all drugs tested, suggesting that the coupling between 5-HT1A receptors and inhibition of cyclic AMP accumulation in HeLa cells is very tight. There were, however, significant variations in both the level of agonism and the potency of a number of compounds when calcium mobilization and the inhibition of cyclic AMP accumulation were compared. Especially in HA7 cells which express lower receptor levels, a number of drugs failed to display agonism (e.g. buspirone or MDL 73005), whereas in HA6 cells they acted as partial agonists. Together, the data show that functional responses mediated by the same receptor can vary rather dramatically depending on receptor density and/or on the effector system involved. Interestingly, 5-HT1A receptor-mediated inhibition of adenylate cyclase activity measured in calf hippocampal membranes shows very similar degrees of potency and intrinsic activity for a number of compounds that have been tested on the inhibition of cyclic AMP accumulation in HeLa cells, suggesting that the very tight coupling observed in the recombinant system may apply to native 5-HT1A receptors.
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PMID:Inhibition of cAMP accumulation via recombinant human serotonin 5-HT1A receptors: considerations on receptor effector coupling across systems. 922 66

Serotonin acts on 5-hydroxytryptamine (5-HT)1B-like receptors in isolated rabbit ear artery precontracted with phenylephrine (PHE). These receptors are inactive, or "silent," in untreated vessels. Ear artery rings were mounted in tissue baths for the measurement of isometric contraction to further characterize these 5-HT1B-like receptors. The 5-HT1-selective receptor agonist sumatriptan failed to contract the untreated ear artery rings but caused a powerful, concentration-dependent contraction in PHE-precontracted vessels. The 5-HT1A/rat 1B receptor antagonist propranolol (1 microM) had no effect, whereas the 5-HT1B receptor antagonists rauwolscine (0.1 microM) and GR127935 (1-100 nM) markedly inhibited the contraction to sumatriptan. In vessels precontracted with phenylephrine, nifedipine reduced and calcium-free medium abolished the contractile response to serotonin. Relaxation to the adenylate cyclase activator forskolin was studied in contracted ear artery rings. Low concentrations (0.1-0.3 microM) of forskolin rapidly and completely relaxed ear artery rings contracted with PHE. In contrast, when PHE-precontracted vessels were contracted with either serotonin or sumatriptan, forskolin caused little or no relaxation at low concentrations and only partial relaxation at 10- to 30-fold higher concentrations. The resistance of these vessels to relaxation by forskolin was markedly reduced in the presence of GR127935 or in ear artery rings from pertussis toxin-treated rabbits. However, pertussis toxin treatment had no effect on the contractile response of PHE-precontracted ear artery rings to serotonin. It is concluded that the silent 5-HT1-like receptor of rabbit ear artery closely resembles the 5-HT1B receptor subtype. This receptor is inversely coupled to adenylate cyclase through a pertussis toxin-sensitive G protein; however, this coupling is unlikely to contribute to the serotonin-induced contraction of PHE-precontracted ear artery rings. Instead, this contraction is mediated at the second-messenger level by pertussis toxin-insensitive influx of calcium.
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PMID:Pharmacological characterization of the "silent" 5-hydroxytryptamine1B-like receptors of rabbit ear artery. 935 82

Alterations in the function of the neurotransmitter serotonin (5-HT) have been implicated in several neurobehavioral disorders, including depression, anxiety as well as a well-known disorder of aging, Alzheimer's disease. Age-dependent changes in the serotonergic system include a loss of 5-HT-containing fibers in brain areas which contain high levels of 5-HT1A receptors. Other changes with aging include decreased 5-HT levels, increases in monoamine oxidase (the major 5-HT degrading enzyme), and decreases in the density of 5-HT receptors. While age-related declines in the number of 5-HT1B and 5-HT2 receptors have been reported, little information is available describing the region-specific effects of aging on the functional dynamics of equilibrium binding at 5-HT receptors, including the 5-HT1A receptor subtype. For example, there are limited data showing a decrease in the maximal binding capacity (Bmax) of 5-HT1A receptors in the aging cortex of humans. However, changes in affinity (Kd) for this receptor subtype as a function of age and brain region have not been fully investigated. Other reports have failed to indicate age-related modifications in human and rat brain tissue 5-HT1A binding parameters. In contrast, electrophysiological studies suggest that the physiological function of the 5-HT1A receptor population is altered with aging. Therefore, to elucidate region-specific 5-HT1A receptor binding characteristics in aging rats, we have utilized a neurotoxic agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) to irreversibly inactivate 5-HT1A receptors. In this way, subsequent age-related changes that occur in 5-HT1A receptor binding characteristics may be investigated. EEDQ is an alkylating agent which irreversibly inactivates serotonergic receptors which are coupled to G proteins. This compound is appropriate for examining the binding profile of several 5-HT receptors, including the 5-HT1A receptor. The 5-HT1A binding site is among the most sensitive of the serotonergic receptor subtypes to inactivation by EEDQ and is also negatively coupled to adenylate cyclase via interaction with a Gi protein. Thus, EEDQ administration is a useful neurotoxicant to examine the relationship between aging and binding characteristics of 5-HT1A receptors. In addition, using EEDQ to inactivate 5-HT1A binding sites, we can further investigate the extent to which receptor binding characteristics (Bmax and Kd) return to baseline levels (i.e., recover) in an age- and brain region-dependent manner following a neurotoxic insult. That is, the age- and region-dependent recovery of 5-HT1A receptors may be monitored in a time-dependent manner to determine receptor turnover parameters, including receptor synthesis and degradation rate constants, and half-life values. Following receptor inactivation by EEDQ, 5-HT1A receptors repopulate (i.e., return to baseline levels) with time and exhibit region-specific turnover rates. Therefore, EEDQ administration is an effective pharmacological tool to investigate region-specific differences in 5-HT1A receptor turnover characteristics. Likewise, by utilizing this neurotoxicant the cellular mechanisms by which pharmacological agents interact with central 5-HT receptors and produce their effects in the aging brain can be addressed. We will illustrate the application of the neurotoxicant EEDQ to irreversibly inactivate 5-HT1A receptors. Following EEDQ administration, region-specific changes in 5-HT1A binding characteristics, including receptor density and drug affinity, and kinetics of receptor recovery will be demonstrated by Scatchard analyses and calculations of the recovery of these receptor populations illustrated. Based on the presence of high densities of 5-HT1A receptors in the hippocampus and frontal cortex, these brain regions will be studied for comparisons of both age- and region-specific alterations in receptor binding characteristics.
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PMID:N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) administration for studies of 5-HT1A receptor binding site inactivation and turnover. 938 17

The aminomethylchroman derivative BAY x 3702 (R-(-)-2-[4-[(chroman-2-ylmethyl)-amino]-butyl]-1,1-dioxo-benzo[d] isothiazolone hydrochloride) is a new high affinity 5-hydroxytryptamine (5-HT)1A receptor ligand [calf hippocampus: Ki: 0.19 nM; reference compounds 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and ipsapirone: 0.98 and 2.56, respectively; rat cortex: 0.24 nM; rat hippocampus: 0.58 nM; human cortex and recombinant 5-HT1A receptors: 0.25 and 0.4 nM, respectively]. BAY x 3702 bound also with relatively high to moderate affinity to the following receptors: alpha-1 and alpha-2 adrenergic (Ki: 6 and 7 nM, respectively); 5-HT7- and 5-HT1D (7 and 36 nM); dopamine D2- and D4 (48 and 91 nM); sigma sites (176 nM) and 5-HT2C (310 nM); others: > 10 microM, as obtained in more than 50 different binding assays. In the forskolin-stimulated adenylate cyclase assay in rat hippocampal tissue, a model of postsynaptic 5-HT1A receptor function, BAY x 3702 was a potent 5-HT1A receptor full agonist (IC50: 1.9 nM; 8-OH-DPAT: 25.3 nM, full agonist; ipsapirone: partial agonist) and its effects could be completely blocked by the 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xan e carboxamide trihydrochloride (WAY-100635). At those receptors where BAY x 3702 bound with lower affinity, the compound appeared to be either an agonist (5-HT1D receptors) or an antagonist (alpha-1, alpha-2 and D2 receptors). In a rat brain slice preparation containing the dorsal raphe nucleus (DRN), a model of somatodendritic 5-HT1A receptor function, BAY x 3702 inhibited potently (1 nM) neuronal firing. Also in vivo, BAY x 3702 (0.5 microgram/kg, i.v.) was found to suppress 5-HT neuronal firing in the DRN of anesthetized rats. In both electrophysiological assays BAY x 3702 was more potent than 8-OH-DPAT and ipsapirone; the potency difference being about 1 and 2 orders of magnitude, respectively. In rats trained to discriminate 8-OH-DPAT (0.1 mg/kg, i.p.) in a drug discrimination procedure, complete generalization was obtained with BAY x 3702 (ED50: 0.022 mg/kg, i.p. and 0.38 mg/kg, p.o.; 8-OH-DPAT: 0.028 mg/kg, i.p. and ipsapirone: 0.44 mg/kg, i.p.). In the rat hypothermia model BAY x 3702 induced a WAY-100635-reversible effect and the compound had a higher potency and intrinsic activity than 8-OH-DPAT and ipsapirone (ED50: 0.25 mg/kg, i.p. and 5.4 mg/kg, p.o., respectively; 8-OH-DPAT: 1.1 mg/kg, i.p. and ipsapirone: 6.2 mg/kg, i.p.). BAY x 3702 induced a stimulation of plasma ACTH levels in the rat; the effect being again more pronounced than that of ipsapirone (ED50: 7.5 and 25.3 mg/kg, p.o., respectively). It is concluded that BAY x 3702 is a relatively selective 5-HT1A receptor agonist with high potency and intrinsic activity.
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PMID:Characterization of the aminomethylchroman derivative BAY x 3702 as a highly potent 5-hydroxytryptamine1A receptor agonist. 949 70

Coated vesicles prepared from bovine brain cerebral cortex exhibited [3H]5-hydroxytryptamine (5-HT, serotonin) and [3H]spiperone binding activities. The binding activities were localized in the inner core vesicles. Binding reached an equilibrium level by 30-45 min at 30 degreesC, and was reversed by the addition of 100 microM 5-HT for [3H]5-HT binding or 10 microM ketanserin for [3H]spiperone binding. The saturation binding experiments indicated a single class of binding sites for [3H]5-HT and [3H]spiperone with apparent Kd values of 2.4 and 1.75 nM, respectively. The binding of [3H]5-HT was displaced by 5-HT and 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), but not by ketanserin. The binding of [3H]spiperone was displaced by spiperone and ketanserin but not by 5-HT or 8-OH-DPAT even at 1 mM. The coated vesicles were shown by immunoblotting assay to contain alpha-subunits of GTP-binding proteins, Galphas, Galphai2, Galphai3, Galphao and Galphaq/11. Forskolin-stimulated adenylate cyclase activity in the coated vesicles was inhibited to 80% of the control level by 5-HT or 8-OH-DPAT. These results suggested that 5-HT1A and 5-HT2A receptors are present in bovine brain coated vesicles and that the 5-HT1A receptors are coupled to adenylate cyclase activity via GTP binding proteins.
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PMID:Characterization of [3H]5-hydroxytryptamine and [3H]spiperone binding sites in clathrin-coated vesicles from bovine brain. 962 54

A series of novel 6-fluorochroman derivatives was prepared and evaluated as antagonists for the 5-HT1A receptor. N-2-[[(6-Fluorochroman-8-yl)oxy]ethyl]-4-(4-methoxyphenyl)butylami ne (3; J. Med. Chem. 1997, 40, 1252-1257) was chosen as a lead, and structural modifications were done on the aliphatic portion of the chroman ring, the tether linking the middle amine and the terminal aromatic ring, the aromatic ring, and lastly the amine. Radioligand binding assays proved that the majority of the novel compounds behaved as good to excellent ligands at the 5-HT1A receptor, some of which were selective with respect to alpha1-adrenergic and D2-dopaminergic receptors. The antagonist activity of the compounds was assessed in the forskolin-stimulated adenylate cyclase assays in CHO cells expressing the human 5-HT1A receptors. Among the modifications attempted, introduction of an oxo or an optically active hydroxy moiety at the chroman C-4 position was effective in ameliorating the receptor selectivity. Six analogues were selected through the in vitro screens and further evaluated for their in vivo activities. A 4-oxochroman derivative (31n), having a terminal 1, 3-benzodioxole ring, demonstrated antagonist activities toward 8-OH-DPAT-induced behavioral and electrophysiological responses in rats.
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PMID:Synthesis and pharmacological characterization of novel 6-fluorochroman derivatives as potential 5-HT1A receptor antagonists. 966 67

The rat ventral prostate possesses specific 5-hydroxytryptamine (5-HT1A) receptors coupled to adenylate cyclase. In vivo treatment of rats or in vitro preincubation of minced prostatic tissue with the 5-HT1A receptor agonist 8-hydroxy-2-(di-N-propylamino)-tetralin (8-OH-DPAT) in different experimental conditions shows the possibility of desensitisation mechanisms with switching from inhibitory to stimulatory pattern on adenylate cyclase activity. As in the majority of systems, we observed the inhibition of forskolin-stimulated adenylate cyclase activity as a functional correlate of 5-HT1A receptor activation. A similar feature occurred when the direct stimulation of the enzyme by the diterpene was replaced by a receptor-mediated activation with the neuropeptide vasoactive intestinal peptide. Furthermore, 8-OH-DPAT stimulated nitric oxide synthase (NOS) activity in a dose-dependent manner. Thus, serotonin appears to be able to act in the rat prostate gland through specific 5-HT1A receptors coupled to a complex system of signal transduction involving an inhibitory response of adenylate cyclase that can become stimulatory, as well as an enhancement of NOS activity.
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PMID:5-hydroxytryptamine1A receptor-mediated effects on adenylate cyclase and nitric oxide synthase activities in rat ventral prostate. 979 57

The opossum kidney (OK) cell line has been shown previously to express endogenous 5-HT1B receptors which negatively couple to adenylate cyclase. Since other Gi-linked receptors have been shown to inhibit adenylate cyclase and to elevate intracellular calcium concentrations ([Ca2+]i), studies were initiated to determine whether native opossum 5-HT1B receptors could also display dual coupling to these signal transduction mechanisms. Saturation studies using [125I](-)-iodocyanopindolol ([125I]CYP) to radiolabel the 5-HT1B receptor in OK cell membranes (in the presence of 3 microM (-)-isoproterenol to mask beta-adrenergic receptors) yielded an equilibrium dissociation constant (pKd) of 10.04 and binding site density (Bmax) of 55 fmol/mg protein. Exposure of intact OK cells to 5-HT, CP 93,129, a selective rodent 5-HT1B receptor agonist, and (+/-)-cyanopindolol, a mixed 5-HT1A/1B receptor agonist/antagonist, produced concentration-dependent inhibitions of forskolin (3 MM)-stimulated cAMP accumulation (FSCA; Emax=90-95%) and elevations of [Ca2+]i (Emax approximately 200 nM increase above basal levels). Agonist potencies (pEC50) ranged from 9.7 to 8.1 and were comparable between the two second messenger assays, although slightly higher agonist potencies (approximately three-fold) were observed in the cAMP assay. GR 127,935, a selective 5-HT1B/1D receptor antagonist, behaved as a strong partial agonist in both the cAMP and calcium assays, with an intrinsic activity of 0.7 relative to 5-HT. Methiothepin, a nonselective 5-HT receptor antagonist, competitively antagonized the inhibitory cAMP response elicited by CP 93,129, yielding an apparent pKb value of 7.3. Methiothepin (10 microM) completely antagonized the stimulatory calcium response evoked by a saturating concentration of CP 93,129 (100 nM). Pertussis toxin pretreatment blocked the CP 93,129-induced inhibition of FSCA and elevation of [Ca2+]i in OK cells, indicating the involvement of Gi/o proteins in transducing these second messenger responses. The agonist properties of (+/-)-cyanopindolol and GR 127,935 observed in both second messenger assays suggests that a large degree of receptor reserve may be present, even though 5-HT1B receptor expression is low in OK cells. The OK cell line continues to serve as a model system to investigate 5-HT1B receptor-mediated signaling events.
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PMID:Native 5-HT1B receptors expressed in OK cells display dual coupling to elevation of intracellular calcium concentrations and inhibition of adenylate cyclase. 984 Apr 17

Ziprasidone is a novel antipsychotic agent which binds with high affinity to 5-HT1A receptors (Ki = 3.4 nM), in addition to 5-HT1D, 5-HT2, and D2 sites. While it is an antagonist at these latter receptors, ziprasidone behaves as a 5-HT1A agonist in vitro in adenylate cyclase measurements. The goal of the present study was to examine the 5-HT1A properties of ziprasidone in vivo using as a marker of central 5-HT1A activity the inhibition of firing of serotonin-containing neurons in the dorsal raphe nucleus. In anesthetized rats, ziprasidone dose-dependently slowed raphe unit activity (ED50 = 300 micrograms/kg i.v.) as did the atypical antipsychotics clozapine (ED50 = 250 micrograms/kg i.v.) and olanzapine (ED50 = 1000 micrograms/kg i.v.). Pretreatment with the 5-HT1A antagonist WAY-100,635 (10 micrograms/kg i.v.) prevented the ziprasidone-induced inhibition; the same dose of WAY-100,635 had little effect on the inhibition produced by clozapine and olanzapine. Because all three agents also bind to alpha 1 receptors, antagonists of which inhibit serotonin neuronal firing, this aspect of their pharmacology was assessed with desipramine (DMI), a NE re-uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity. DMI (5 mg/kg i.v.) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine. These profiles suggest a mechanism of action for each agent, 5-HT1A agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine. The 5-HT1A agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions.
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PMID:Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine: inhibition of dorsal raphe cell firing and the role of 5-HT1A receptor activation. 1051 58


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