共查询到20条相似文献,搜索用时 9 毫秒
1.
K L Meagher R E Mewshaw D A Evrard P Zhou D L Smith R Scerni T Spangler S Abulhawa X Shi L E Schechter T H Andree 《Bioorganic & medicinal chemistry letters》2001,11(14):1885-1888
A series of indolylcyclohexylamines possessing potent and selective serotonin reuptake inhibition is reported. The most interesting compounds proved to have subnanomolar 5-HT transporter activity, and exhibited moderate 5-HT(1A) affinity. 相似文献
2.
Zhou D Zhou P Evrard DA Meagher K Webb M Harrison BL Huryn DM Golembieski J Hornby GA Schechter LE Smith DL Andree TH Mewshaw RE 《Bioorganic & medicinal chemistry》2008,16(14):6707-6723
Based on the previously reported discovery lead, 3-(cis-4-(4-(1H-indol-4-yl)piperazin-1-yl)cyclohexyl)-5-fluoro-1H-indole (2), a series of related arylpiperazin-4-yl-cyclohexyl indole analogs were synthesized then evaluated as 5-HT transporter inhibitors and 5-HT(1A) receptor antagonists. The investigation of the structure-activity relationships revealed the optimal pharmacophoric elements required for activities in this series. The best example from this study, 5-(piperazin-1-yl)quinoline analog (trans-20), exhibited equal binding affinities at 5-HT transporter (K(i)=4.9nM), 5-HT(1A) receptor (K(i)=6.2nM) and functioned as a 5-HT(1A) receptor antagonist. 相似文献
3.
Zhou D Harrison BL Shah U Andree TH Hornby GA Scerni R Schechter LE Smith DL Sullivan KM Mewshaw RE 《Bioorganic & medicinal chemistry letters》2006,16(5):1338-1341
The design, synthesis, and structure-activity relationship of two novel classes of benzoxazine derivatives with dual selective serotonin reuptake inhibitors and 5-HT(1A) receptor activities are described. 相似文献
4.
Evrard DA Zhou P Yi SY Zhou D Smith DL Sullivan KM Hornby GA Schechter LE Andree TH Mewshaw RE 《Bioorganic & medicinal chemistry letters》2005,15(4):911-914
Derivatives of the serotonin reuptake inhibitor 4-(5-fluoro-1H-indol-3-yl)cyclohexylamine, in which serotonin 1A (5-HT(1A)) receptor pharmacophoric elements are incorporated, are reported. Analogs exhibiting affinity for both the serotonin transporter and the 5-HT(1A) receptor are described. Compounds containing 1-(4-indolyl)piperazine and 2-(1H-indol-4-yloxy)ethylamine are promising leads for further SAR studies. 相似文献
5.
A M Gardier A C Trillat I Malagié D David M Hasco?t M C Colombel P Jolliet C Jacquot R Hen M Bourin 《Comptes rendus de l'Académie des sciences. Série III, Sciences de la vie》2001,324(5):433-441
We used knockout mice and receptor antagonist strategies to investigate the contribution of the serotonin (5-hydroxytryptamine, 5-HT) 5-HT1B receptor subtype in mediating the effects of selective serotonin reuptake inhibitors (SSRIs). Using in vivo intracerebral microdialysis in awake mice, we show that a single systemic administration of paroxetine (1 or 5 mg/kg, i.p.) increased extracellular serotonin levels [5-HT]ext in the ventral hippocampus and frontal cortex of wild-type and mutant mice. However, in the ventral hippocampus, paroxetine at the two doses studied induced a larger increase in [5-HT]ext in knockout than in wild-type mice. In the frontal cortex, the effect of paroxetine was larger in mutants than in wild-type mice at the 1 mg/kg dose but not at 5 mg/kg. In addition, either the absence of the 5-HT1B receptor or its blockade with the mixed 5-HT1B/1D receptor antagonist, GR 127935, potentiates the effect of a single administration of paroxetine on [5-HT]ext more in the ventral hippocampus than in the frontal cortex. Furthermore, we demonstrate that SSRIs decrease immobility in the forced swimming test; this effect is absent in 5-HT1B knockout mice and blocked by GR 127935 in wild-type suggesting therefore that activation of 5-HT1B receptors mediate the antidepressant-like effects of SSRIs. Taken together these data demonstrate that 5-HT1B autoreceptors appear to limit the effects of SSRI on dialysate 5-HT levels particularly in the hippocampus while presynaptic 5-HT1B heteroreceptors are likely to be required for the antidepressant activity of SSRIs. 相似文献
6.
Lovell PJ Blaney FE Goodacre CJ Scott CM Smith PW Starr KR Thewlis KM Vong AK Ward SE Watson JM 《Bioorganic & medicinal chemistry letters》2007,17(4):1033-1036
Investigation of halogen substitution in lead compound 1 has led to the identification of analogues which combine high affinity for 5-HT(1A) receptors and potent serotonin reuptake inhibitory activity. Several compounds show an improved selectivity over 5-HT(1B) and 5-HT(1D) receptors and a superior pharmacokinetic profile in the rat. 相似文献
7.
Trillat AC Malagié I Bourin M Jacquot C Hen R Gardier AM 《Comptes rendus des séances de la Société de biologie et de ses filiales》1998,192(6):1139-1147
We use the knockout mice strategy to investigate the contribution of the 5-HT1B receptor in mediating the effects of selective serotonin reuptake inhibitors (SSRI). Using microdialysis in awake 129/Sv mice, we show that the absence of the 5-HT1B receptor in mutant mice (KO 1B -/-) potentiated the effect of paroxetine on extracellular 5-HT levels in the ventral hippocampus, but not in the frontal cortex compared to wild-type mice (WT). Furthermore, using the forced swimming test, we demonstrate that SSRIs decreased immobility of WT mice, and this effect is absent in KO 1B -/- mice showing therefore that activation of 5-HT1B receptors mediate the antidepressant-like effects of SSRIs. Taken together these findings suggest that 5-HT1B autoreceptors limit the effects of SSRI particularly in the hippocampus while postsynaptic 5-HT1B receptors are required for the antidepressant activity of SSRIs. 相似文献
8.
Timms GH Boot JR Broadmore RJ Carney SL Cooper J Findlay JD Gilmore J Mitchell S Moore NA Pullar I Sanger GJ Tomlinson R Tree BB Wedley S 《Bioorganic & medicinal chemistry letters》2004,14(10):2469-2472
Incorporation of an SRI (serotonin reuptake inhibitor) pharmacophore into a selective 5-HT(1D) agonist has led to the discovery of a molecule having both 5-HT(1D) antagonist and SRI activity. RPS methodology was used to develop the SAR and identify potential approaches to reduce unwanted adrenergic alpha 1 and dopamine D(2) cross-reactivities. 相似文献
9.
Derek J. Denhart Jeffrey A. Deskus Jonathan L. Ditta Qi Gao H. Dalton King Edward S. Kozlowski Zhaoxing Meng Melissa A. LaPaglia Gail K. Mattson Thaddeus F. Molski Matthew T. Taber Nicholas J. Lodge Ronald J. Mattson John E. Macor 《Bioorganic & medicinal chemistry letters》2009,19(15):4031-4033
A series of racemic 3-(trans-2-aminomethylcyclopentyl)indoles was synthesized and found to have potent binding to the human serotonin transporter (hSERT). The most active analog was synthesized stereospecifically and the active enantiomer was shown to have high affinity binding to hSERT. 相似文献
10.
Thomas Ryckmans Laurent Balan?on Olivier Berton Christophe Genicot Yves Lamberty Benedicte Lallemand Patrick Pasau Nathalie Pirlot Luc Quéré Patrice Talaga 《Bioorganic & medicinal chemistry letters》2002,12(2):261-264
Compounds combining NK(1) antagonism and serotonin reuptake inhibition are described, and potentially represent a new generation of antidepressants. Compound 24 displays good affinities for both the NK(1) receptor and the serotonin reuptake site (32 and 25 nM, respectively). 相似文献
11.
Bromidge SM Arban R Bertani B Borriello M Capelli AM Di-Fabio R Faedo S Gianotti M Gordon LJ Granci E Pasquarello A Spada SK Worby A Zonzini L Zucchelli V 《Bioorganic & medicinal chemistry letters》2010,20(23):7092-7096
5-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2(1H)-quinolinones and 3,4-dihydro-2(1H)-quinolinones have been identified with different combinations of 5-HT(1) autoreceptor antagonist and hSerT potencies and excellent rat PK profiles. The availability of tool compounds with a range of profiles at targets known to play a key role in the control of synaptic 5-HT levels will allow exploration of different pharmacological profiles in a range of animal behavioral and disease models. 相似文献
12.
Ryckmans T Berton O Grimée R Kogej T Lamberty Y Pasau P Talaga P Genicot C 《Bioorganic & medicinal chemistry letters》2002,12(21):3195-3198
The synthesis, structure-affinity relationship and activity of benzyloxyphenethyl piperazine derivatives combining NK(1) antagonism and serotonin reuptake inhibition is described. Compound 7u was shown to be active in animal models of 5-HT reuptake inhibition and central NK(1) receptor blockade, and was demonstrated to be orally active in an integrated model sensitive to both mechanisms. This class of compounds potentially represents a new generation of antidepressants. 相似文献
13.
Torrado A Lamas C Agejas J Jiménez A Diaz N Gilmore J Boot J Findlay J Hayhurst L Wallace L Broadmore R Tomlinson R 《Bioorganic & medicinal chemistry》2004,12(20):5277-5295
A series of compounds combining the naphthylpiperazine and thienopyran scaffolds has been prepared and evaluated for 5-HT reuptake inhibition with 5-HT1D antagonist activity. The design of these compounds has been based on the 'overlapping type' strategy where two pharmacophores are linked in a single molecule. The resultant dual pharmacological profile has the potential to deliver a more efficient treatment for depression. 相似文献
14.
A G Saltzman B Morse M M Whitman Y Ivanshchenko M Jaye S Felder 《Biochemical and biophysical research communications》1991,181(3):1469-1478
We report the cloning and the deduced amino acid sequence of cDNAs encoding both the human serotonin 5-HT2 and 5-HT1C receptors. The human 5-HT2 and 5-HT1C receptors shared 87% and 90% amino acid homology, respectively, with their rat counterparts. The most divergent regions of the 5-HT2 receptor between human and rat were the N-terminal extracellular domain (75% homology) and the C-terminal intracellular domain (67% homology between amino acids 426-474). The greatest variability between the human and rat 5-HT1C receptors were at the N-terminal extracellular domain (78% homology) and the third cytoplasmic loop (71% homology). The availability of the cloned human 5-HT2 and 5-HT1C receptors will help facilitate the further understanding of the molecular pharmacology and physiology of these receptors. 相似文献
15.
Takeuchi K Kohn TJ Honigschmidt NA Rocco VP Spinazze PG Hemrick-Luecke SK Thompson LK Evans DC Rasmussen K Koger D Lodge D Martin LJ Shaw J Threlkeld PG Wong DT 《Bioorganic & medicinal chemistry letters》2006,16(9):2347-2351
A series of 1-aryloxy-3-piperidinylpropan-2-ols possessing potent dual 5-HT1A receptor antagonism and serotonin reuptake inhibition was discovered. 1-(1H-Indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols exhibited selective and high affinities at the 5-HT1A receptor and serotonin reuptake site in vitro. In vivo evaluation of this series of compounds demonstrated elevated extracellular serotonin levels from the basal and quick recovery of neuron firing that was presumably suppressed by the initial acute activation of 5-HT1A somatodendritic autoreceptors. 相似文献
16.
Atkinson PJ Bromidge SM Duxon MS Gaster LM Hadley MS Hammond B Johnson CN Middlemiss DN North SE Price GW Rami HK Riley GJ Scott CM Shaw TE Starr KR Stemp G Thewlis KM Thomas DR Thompson M Vong AK Watson JM 《Bioorganic & medicinal chemistry letters》2005,15(3):737-741
Starting from a high throughput screening hit, a series of 3,4-dihydro-2H-benzoxazinones has been identified with both high affinity for the 5-HT(1A) receptor and potent 5-HT reuptake inhibitory activity. The 5-(2-methyl)quinolinyloxy derivative combined high 5-HT(1A/1B/1D) receptor affinities with low intrinsic activity and potent inhibition of the 5-HT reuptake site (pK(i)8.2). This compound also had good oral bioavailability and brain penetration in the rat. 相似文献
17.
BACKGROUND: Serotonin (5-HT) has negative immunoregulatory effects by reducing the interferon-gamma (IFNgamma)/interleukin-10 (IL-10) production ratio by stimulated immune cells. Leukocytes have functional 5-HT1B receptors. 5-HT moduline, an endogenous 5-HT1B receptor antagonist, may antagonize the 5-HT1B agonist-induced proliferation of immune cells. AIMS: To examine the effects of 5-HT moduline on the stimulated production of IFNgamma, tumor necrosis factor alpha (TNFalpha) and IL-10. RESULTS: 5-HT moduline, 10(-6) M and 10(-5)M, significantly reduced the production of IFNgamma and the IFNgamma/IL-10 ratio. 5-HT moduline 10(-5)M significantly reduced the production of TNFalpha. The combination of 5-HT, 15 microg/mL, with 5-HT moduline, 10(-6)M and 10(-5)M, further decreases the IFNgamma/IL-10 production ratio. INTERPRETATION: 5-HT moduline has negative immunoregulatory effects. 相似文献
18.
Measurements of serotonin (5-HT), dopamine (DA), and noradrenaline, and of 5-HT and DA metabolites, were obtained by HPLC from 16 brain regions and the spinal cord of 5-HT(1A) or 5-HT(1B) knockout and wild-type mice of the 129/Sv strain. In 5-HT(1A) knockouts, 5-HT concentrations were unchanged throughout, but levels of 5-HT metabolites were higher than those of the wild type in dorsal/medial raphe nuclei, olfactory bulb, substantia nigra, and locus coeruleus. This was taken as an indication of increased 5-HT turnover, reflecting an augmented basal activity of midbrain raphe neurons and consequent increase in their somatodendritic and axon terminal release of 5-HT. It provided a likely explanation for the increased anxious-like behavior observed in 5-HT(1A) knockout mice. Concomitant increases in DA content and/or DA turnover were interpreted as the result of a disinhibition of DA, whereas increases in noradrenaline concentration in some territories of projection of the locus coeruleus could reflect a diminished activity of its neurons. In 5-HT(1B) knockouts, 5-HT concentrations were lower than those of the wild type in nucleus accumbens, locus coeruleus, spinal cord, and probably also several other territories of 5-HT innervation. A decrease in DA, associated with increased DA turnover, was measured in nucleus accumbens. These changes in 5-HT and DA metabolism were consistent with the increased aggressiveness and the supersensitivity to cocaine reported in 5-HT(1B) knockout mice. Thus, markedly different alterations in CNS monoamine metabolism may contribute to the opposite behavioral phenotypes of these two knockouts. 相似文献
19.
Bromidge SM Bertani B Borriello M Faedo S Gordon LJ Granci E Hill M Marshall HR Stasi LP Zucchelli V Merlo G Vesentini A Watson JM Zonzini L 《Bioorganic & medicinal chemistry letters》2008,18(20):5653-5656
Investigation of a series 6-[2-(4-aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones has led to the discovery of potent 5-HT(1A/1B/1D) receptor antagonists with and without additional SerT affinity. Modulation of the different target activities gave compounds with a range of profiles suitable for further in vivo characterization. 相似文献
20.
Levin JI Chen J Du M Hogan M Kincaid S Nelson FC Venkatesan AM Wehr T Zask A DiJoseph J Killar LM Skala S Sung A Sharr M Roth C Jin G Cowling R Mohler KM Black RA March CJ Skotnicki JS 《Bioorganic & medicinal chemistry letters》2001,11(16):2189-2192
A novel series of anthranilic acid-based inhibitors of MMP-1, MMP-9, MMP-13, and TACE was prepared and evaluated. Selective inhibitors of MMP-9, MMP-13, and TACE were identified, including the potent, orally active MMP-13 inhibitor 4p. 相似文献