共查询到20条相似文献,搜索用时 15 毫秒
1.
《Bioorganic & medicinal chemistry》2016,24(2):130-139
The N-alkylation of the sulfonamide moiety, in a group of arylsulfonamide derivatives of (aryloxy)ethyl piperidines, may be considered as a strategy for the design of selective 5-HT7 receptor ligands or multifunctional agents to extend a polypharmacological approach to the treatment of complex diseases. The study allowed for the identification of 31 (1-methyl-N-{1-[2-(2-(t-butyl)phenoxy)ethyl]piperidin-4-yl}-N-cyclopropylmethyl-1H-pyrazole-4-sulfonamide), a potent and selective 5-HT7 receptor antagonist and 33 (1-methyl-N-{1-[2-(biphenyl-2-yloxy)ethyl]piperidin-4-yl}-N-cyclopropylmethyl-1H-pyrazole-4-sulfonamide), as multimodal 5-HT/dopamine receptor ligand, as 5-HT2A/5-HT7/D2 receptor antagonists. Both selected compounds were evaluated in vivo in a forced swim test (FST) in mice and in a novel object recognition (NOR) task in rats, demonstrating distinct antidepressant-like and pro-cognitive properties (MED = 1.25 mg/kg and 1 mg/kg, ip, respectively). These findings warrant further studies to explore the therapeutic potential of N-alkylated arylsulfonamides for the treatment of CNS disorders. 相似文献
2.
A novel series of arylsulfonylaminomethyl-3-(1-phenyl-5-isopropyl)pyrazoles was evaluated for serotonin receptor subtype 6 (5-HT6R) antagonistic effects in vitro. We also investigated their neuropathic pain-alleviating effects in vivo using a rat spinal nerve ligation (SNL) model. Bicyclic aromatic sulfonamino groups, such as naphthalene and quinolin-substituted derivatives, showed good 5-HT6 inhibitory activity in vitro. Among them, selected compounds, 12 and 13, having 8-quinoylsulfonamino groups, showed potent neuropathic pain-alleviating effects in the rat model. 相似文献
3.
Aranapakam M. Venkatesan O. Dos Santos John Ellingboe Deborah A. Evrard Boyd L. Harrison Deborah L. Smith Rosemary Scerni Geoffrey A. Hornby Lee E. Schechter Terrence H. Andree 《Bioorganic & medicinal chemistry letters》2010,20(3):824-827
Several benzofuran derivatives linked to a 3-indoletetrahydropyridine through an alkyl chain were prepared and evaluated for serotonin transporter and 5-HT1A receptor affinities. Their design, synthesis and structure–activity relationships are described. 相似文献
4.
Austin NE Avenell KY Boyfield I Branch CL Coldwell MC Hadley MS Jeffrey P Johns A Johnson CN Nash DJ Riley GJ Smith SA Stacey RC Stemp G Thewlis KM Vong AK 《Bioorganic & medicinal chemistry letters》1999,9(2):179-184
Using clearance and brain penetration studies as a screen, tetrahydroisoquinoline 3 was identified as a lead having low clearance in rats (CLb 20 ml/min/kg). Introduction of a 7-CF3SO2O- substituent into the tetrahydroisoquinoline, followed by replacement of the biphenylamido group of 3 by a 3-indolylpropenamido group gave 31, having high D3 receptor affinity (pKi 8.4) and 150 fold selectivity over the D2 receptor. 相似文献
5.
Mattsson C Sonesson C Sandahl A Greiner HE Gassen M Plaschke J Leibrock J Böttcher H 《Bioorganic & medicinal chemistry letters》2005,15(19):4230-4234
A series of 2-alkyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles were synthesized and evaluated for their 5-HT6 activity. The most potent agonist in this series was 5-chloro-2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole with an IC50=7.4 nM in 3H-LSD binding and an EC50=1.0 nM in a functional assay measuring production of cyclic AMP. 相似文献
6.
Arora J Bordeleau M Dube L Jarvie K Mazzocco L Peragine J Tehim A Egle I 《Bioorganic & medicinal chemistry letters》2005,15(23):5253-5256
A series of N-[(3S)-1-benzylpyrrolidin-3-yl]-(2-thienyl)benzamides 8 has been prepared and found to bind with high affinity to the human D(4) (hD(4)) and 5-HT(2A) receptors. Several compounds displayed selectivity for these receptors versus hD(2) and alpha(1) adrenergic receptors of over 500-fold. 相似文献
7.
Austin NE Avenell KY Boyfield I Branch CL Hadley MS Jeffrey P Johnson CN Macdonald GJ Nash DJ Riley GJ Smith AB Stemp G Thewlis KM Vong AK Wood M 《Bioorganic & medicinal chemistry letters》2000,10(22):2553-2555
Starting from the dopamine D3 receptor antagonist SB-277011 1, a series of 2,3,4,5-tetrahydro-1H-3-benzazepines has been identified with high affinity for the dopamine D3 receptor and selectivity over the D2 receptor. The 3-acetamido-2-fluorocinnamide derivative 20 gave high D3 receptor affinity (pKi 8.4) with 130-fold selectivity over the 2, receptor. 相似文献
8.
Marchais-Oberwinkler S Nowicki B Pike VW Halldin C Sandell J Chou YH Gulyas B Brennum LT Farde L Wikström HV 《Bioorganic & medicinal chemistry》2005,13(3):883-893
WAY-100635 [N-(2-(1-(4-(2-methoxyphenyl)piperazinyl)ethyl))-N-(2-pyridinyl)cyclohexanecarboxamide] 1 and its O-desmethyl derivative DWAY 2 are well-known high affinity 5-HT(1A) receptor antagonists, which when labeled with carbon-11 (beta+; t(1/2) = 20.4 min) in the carbonyl group are effective radioligands for imaging brain 5-HT(1A) receptors with positron emission tomography (PET). In a search for new 5-HT(1A) antagonists with different pharmacokinetic and metabolic properties, the pyridinyl N-oxide moiety was incorporated into analogs of 1 and 2. NOWAY 3, in which the pyridinyl ring of 1 was oxidized to the pyridinyl N-oxide, was prepared via nucleophilic substitution of 2-[4-(2-methoxyphenyl)piperazin-1-yl]ethylamine on 2-chloropyridine-N-oxide followed by acylation with cyclohexanecarbonyl chloride. 6Cl-NOWAY 4, a more lipophilic (pyridinyl-6)-chloro derivative of 3, was prepared by treating 1-(2-methoxyphenyl)-4-(2-(2-(6-bromo)aminopyridinyl-N-oxide)ethyl)piperazine with cyclohexanecarbonyl chloride for acylation and concomitant chloro for bromo substitution. NEWWAY 5, in which the 2-hydroxy-phenyl group of 2 is replaced with a 2-pyridinyl N-oxide group with the intention of mimicking the topology of 2, was prepared in five steps from 2-(chloroacetylamino)pyridine. N-Oxides 3-5 were found to be high affinity antagonists at 5-HT(1A) receptors, with 3 having the highest affinity and a Ki value (0.22 nM) comparable to that of 1 (0.17 nM). By calculation the lipophilicity of 3 (LogP = 1.87) is lower than that of 1 by 1.25 LogP units while TLC and reverse phase HPLC indicate that 3 has slightly lower lipophilicity than 1. On the basis of these encouraging findings, the N-oxide 3 was selected for labeling with carbon-11 in its carbonyl group and for evaluation as a radioligand with PET. After intravenous injection of [carbonyl-11C]3 into cynomolgus monkey there was very low uptake of radioactivity into brain and no PET image of brain 5-HT(1A) receptors was obtained. Either 3 inadequately penetrates the blood-brain barrier or it is excluded from brain by an active efflux mechanism. Rapid deacylation of 3 was not apparent in vivo; in cynomolgus monkey plasma radioactive metabolites of [carbonyl-11C]3 appeared less rapidly than from the radioligands [carbonyl-11C]1 and [carbonyl-11C]2, which are known to be primarily metabolized by deacylation. Ligand 3 may have value as a new pharmacological tool, but not as a radioligand for brain imaging. 相似文献
9.
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
10.
Egle I MacLean N Demchyshyn L Edwards L Slassi A Tehim A 《Bioorganic & medicinal chemistry letters》2004,14(3):727-729
A series of 3-(2-pyrrolidin-1-ylethyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives (2) has been prepared using parallel synthesis techniques, and their structure-activity relationships studied. High affinity human 5-HT(1B/1D) (h5-HT(1B/1D)) ligands have been identified. 相似文献
11.
Cole DC Ellingboe JW Lennox WJ Mazandarani H Smith DL Stock JR Zhang G Zhou P Schechter LE 《Bioorganic & medicinal chemistry letters》2005,15(2):379-383
A series of N(1)-arylsulfonyl-3-(1,2,3,6-tetrahydropyridin-4-yl)indole derivatives was designed and synthesized. These compounds were shown to have high affinity for the 5-HT(6) receptor. Two analogs, 4-[3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-1-sulfonyl]-phenylamine 15g and 4-[3-(1,2,3,6-tetrahydropyridin-4-yl)-5-methoxy-1H-indole-1-sulfonyl]-phenylamine 15y, had 0.4 and 3.0 nM affinity, respectively, and antagonized the production of adenylate cyclase at sub-nanomolar concentrations. 相似文献
12.
Perrone R Berardi F Colabufo NA Leopoldo M Tortorella V 《Bioorganic & medicinal chemistry》2000,8(5):873-881
In the present paper, we report the synthesis and the binding profiles on 5-HT1A, D2, and alpha1 receptors of 1-substituted-4-[3-(5- or 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine derivatives 19-32 and some related heteroalkyl derivatives 33-35. The results obtained are compared to those previously reported for the 1-phenyl, 1-(2-methoxyphenyl), 1-(2-pyridyl) analogues 2-9. The results pointed out the critical role of the group linked in the N-1 position of the piperazine in terms of 5-HT1A binding affinity. In fact, 1-cyclohexyl, 1-(3-benzisoxazolyl), 1-(benzothiazole-2-carbonyl), 1-(2-benzothiazolyl), 1-(2-quinolyl) substituted piperazines 21-30 displayed moderate or low 5-HT1A receptor affinity; on the contrary, 1-(3-benzisothiazolyl) and 1-(1-naphthalenyl) substituted piperazines 19, 20 and 32 displayed high 5-HT1A receptor affinity, the Ki values being in the subnanomolar range. Furthermore, compounds 19, 20 and 32 demonstrated better selectivity over alpha1 receptors than the reference compounds 2-9. 相似文献
13.
Egle I MacLean N Demchyshyn L Edwards L Slassi A Tehim A 《Bioorganic & medicinal chemistry letters》2003,13(20):3419-3421
A series of (R)-3-(N-methylpyrrolidin-2-ylmethyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives (2) have been prepared using parallel synthesis, and their structure-activity relationship studied. High affinity human 5-HT(1B/1D) (h5-HT(1B/1D)) ligands have been identified. 相似文献
14.
Elzein E Kalla R Li X Perry T Parkhill E Palle V Varkhedkar V Gimbel A Zeng D Lustig D Leung K Zablocki J 《Bioorganic & medicinal chemistry letters》2006,16(2):302-306
A series of new 1,3-dipropyl-8-(1-heteroarylmethyl-1H-pyrazol-4-yl)-xanthine derivatives as A(2B)-AdoR antagonists have been synthesized and evaluated for their binding affinities for the A(2B), A(1), A(2A), and A(3)-AdoRs. 8-(1-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrazol-4-yl)-1,3-dipropyl-1H-purine-2,6(3H,7H)-dione (4) displayed high affinity (K(i)=1 nM) and selectivity for the A(2B)-AdoR versus A(1), A(2A), and A(3)-AdoRs (A(1)/A(2B), A(2A)/A(2B), and A(3)/A(2B) selectivity ratios of 370, 1100, and 480, respectively). The synthesis and SAR of this novel class of compounds are presented herein. 相似文献
15.
Euna Yoo Juhee Yoon Ae Nim Pae Hyewhon Rhim Woo-Kyu Park Jae Yang Kong Hea-Young Park Choo 《Bioorganic & medicinal chemistry》2010,18(4):1665-1675
A novel series of 5-HT2A ligands that contain a (phenylpiperazinyl-propyl)arylsulfonamides skeleton was synthesized. Thirty-seven N-(cycloalkylmethyl)-4-methoxy-N-(3-(4-arylpiperazin-1-yl)propyl)-arylsulfonamide and N-(4-(4-arylpiperazin-1-yl)butan-2-yl)-arylsulfonamide compounds were obtained. The binding of these compounds to the 5-HT2A, 5-HT2C, and 5-HT7 receptors was evaluated. Most of the compounds showed IC50 values of less than 100 nM and exhibited high selectivity for the 5-HT2A receptor. Among the synthesized compounds, 16a and 16d showed good affinity at 5-HT2A (IC50 = 0.7 nM and 0.5 nM) and good selectivity over 5-HT2C (50–100 times) and 5-HT7 (1500–3000 times). 相似文献
16.
Ramakrishna V.S. Nirogi Rajeshkumar Badange Ramasastri Kambhampati Anil Chindhe Amol D. Deshpande Vinaykumar Tiriveedhi Vishwottam Kandikere Nageswararao Muddana Renny Abraham Mukkanti Khagga 《Bioorganic & medicinal chemistry letters》2012,22(24):7431-7435
4-(Piperazin-1-yl methyl)-N1-arylsulfonyl indole derivatives were designed and synthesized as 5-HT6 receptor (5-HT6R) ligands. The lead compound 6a, from this series shows potent in vitro binding affinity, good PK profile, no CYP liabilities and activity in animal models of cognition. 相似文献
17.
Candelore MR Wright MJ Tota LM Milligan J Shei GJ Bergstrom JD Mandala SM 《Biochemical and biophysical research communications》2002,297(3):600-606
It has been reported recently that the phosphorylated form of the immunomodulator FTY720 activates sphingosine 1-phosphate G protein-coupled receptors [1] and [2]. Therefore, understanding the biology of this new class of receptors will be important in clarifying the immunological function of bioactive lysosphingolipid ligands. The S1P4 receptor has generated interest due to its lymphoid tissue distribution. While the S1P4 receptor binds the prototypical ligand, S1P, a survey of other lysosphingolipids demonstrated that 4d-hydroxysphinganine 1-phosphate, more commonly known as phytosphingosine 1-phosphate (PhS1P), binds to S1P4 with higher affinity. Using radiolabeled S1P (S133P), the affinity of PhS1P for the S1P4 receptor is 1.6 nM, while that of S1P is nearly 50-fold lower (119±20 nM). Radiolabeled PhS1P proved to be superior to S133P in routine binding assays due to improved signal-to-noise ratio. The present study demonstrates the utility of a novel radiolabeled probe, PhS133P, for in vitro studies of the S1P4 receptor pharmacology. 相似文献
18.
Park CM Choi JI Choi JH Kim SY Park WK Seong CM 《Bioorganic & medicinal chemistry letters》2011,21(2):698-703
Piperazinyl derivatives of 1-(arylsulfonyl)-2,3-dihydro-1H-quinolin-4-ones have been identified with high binding affinities for 5-HT6 receptor. In particular, 2-methyl-5-(N-methyl-piperazin-1-yl)-1-(naphthalene-2-sulfonyl)-2,3-dihydro-1H-quinolin-4-one (8g) exhibits high binding affinity toward 5-HT6 (IC50 = 8 nM) receptor with good selectivity over other serotonin and dopamine receptors. 相似文献
19.
Novel aryloxy-8-azabicyclo[3.2.1]oct-3-enes with 5-HT transporter and 5-HT1A affinity 总被引:1,自引:0,他引:1
Gilbert AM Coleman T Kodah J Mewshaw RE Scerni R Schechter LE Smith DL Andree TH 《Bioorganic & medicinal chemistry letters》2004,14(21):5281-5284
Joining aryl 8-azabicyclo[3.2.1]oct-3-enes with aryloxyethanes and aryloxypropanes produces novel series of compounds 11 and 12 with potent 5-HT-T affinity and moderately potent 5-HT(1A) affinity. Moreover, several of these compounds possess functional 5-HT(1A) antagonism. Optimal compounds are, 4-indolyloxyethane 21, 4-indolyloxypropanes 25, and 27, which possess potent 5-HT-T affinity (5-HT-T K(i): 21: 1.2nM, 25: 0.54nM, 27: 0.38nM) and good 5-HT(1A) affinity/antagonism (5-HT(1A)K(i), [(35)S]GTPgammaS: E(max) (%): 21: 111.1nM, 0%; 25: 173.2nM, 0%; 27: 107nM, 0%). 相似文献
20.
Kalla RV Elzein E Perry T Li X Gimbel A Yang M Zeng D Zablocki J 《Bioorganic & medicinal chemistry letters》2008,18(4):1397-1401
A series of N-1 monosubstituted 8-pyrazolyl xanthines have been synthesized and evaluated for their affinity for the adenosine receptors (AdoRs). We have discovered two compounds 18 (CVT-7124) and 28 (CVT-6694) that display good affinity for the A(2B) AdoR (K(i)=6 nM and 7 nM, respectively) and greater selectivity for the human A(1), A(2A), and A(3) AdoRs (>1000-, >830-, and >1500-fold; >850-, >700-, and >1280-fold, respectively). CVT-6694 has been shown to block the release of interleukin-6 and monocyte chemotactic protein-1 from bronchial smooth muscle cells (BSMC), a process believed to be promoted by activation of A(2B) AdoR. 相似文献