共查询到20条相似文献,搜索用时 31 毫秒
1.
Morten Jørgensen Pernille N. Jørgensen Claus T. Christoffersen Klaus G. Jensen Thomas Balle Benny Bang-Andersen 《Bioorganic & medicinal chemistry》2013,21(1):196-204
The synthesis and in vitro preclinical profile of a series of 5-heteroaryl substituted analogs of the antipsychotic drug sertindole are presented. Compounds 1-(4-fluorophenyl)-3-(1-methylpiperidin-4-yl)-5-(pyrimidin-5-yl)-1H-indole (Lu AA27122, 3i) and 1-(4-fluorophenyl)-5-(1-methyl-1H-1,2,4-triazol-3-yl)-3-(1-methylpiperidin-4-yl)-1H-indole (3l) were identified as high affinity α1A-adrenoceptor ligands with Ki values of 0.52 and 0.16 nM, respectively, and with a >100-fold selectivity versus dopamine D2 receptors. Compound 3i showed almost equal affinity for α1B- (Ki = 1.9 nM) and α1D-adrenoceptors (Ki = 2.5 nM) as for α1A, as well as moderate affinity for 5-HT1B (Ki = 13 nM) and 5-HT6 (Ki = 16 nM) receptors, whereas 3l showed >40-fold selectivity toward all other targets tested. Based on in vitro assays for assessment of permeability rates and extent, it is predicted that both compounds enter the brain of rats, non-human primates, as well as humans, and as such are good candidates to be carried forward for further evaluation as positron emission tomography (PET) ligands. 相似文献
2.
《Bioorganic & medicinal chemistry letters》2014,24(7):1766-1770
A series of benzoxazole/benzothiazole-2,3-dihydrobenzo[b][1,4]dioxine derivatives (5a–5d and 8a–8j) was synthesized. Compounds were evaluated for binding affinities at the 5-HT1A and 5-HT2A receptors. Antidepressant activities of the compounds were screened using the forced swimming test (FST) and the tail suspension test (TST). The results indicated that the compounds exhibited high affinities for the 5-HT1A and 5-HT2A receptors and showed a marked antidepressant-like activity. Compound 8g exhibited high affinities for the 5-HT1A (Ki = 17 nM) and 5-HT2A (Ki = 0.71 nM) receptors; it also produced a decrease of the immobility time and exhibited potent antidepressant-like effects in the FST and TST in mice. 相似文献
3.
Ayako Moritomo Hiroyoshi Yamada Toshihiro Watanabe Hirotsune Itahana Shinobu Akuzawa Minoru Okada Mitsuaki Ohta 《Bioorganic & medicinal chemistry》2013,21(24):7841-7852
To identify potent dual 5-HT2B and 5-HT7 receptor antagonists, we synthesized a series of novel carbonyl guanidine derivatives and examined their structure–activity relationships. Among these compounds, N-(9-hydroxy-9H-fluorene-2-carbonyl)guanidine (10) had a good in vitro profile, that is, potent affinity for human 5-HT2B and 5-HT7 receptor subtypes (Ki = 1.8 nM and Ki = 17.6 nM, respectively) and high selectivity over 5-HT2A, 5-HT2C, α1, D2 and M1 receptors. Compound 10 also showed a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs when orally administered. 相似文献
4.
Vattoly J. Majo Matthew S. Milak Jaya Prabhakaran Pratap Mali Lyudmila Savenkova Norman R. Simpson J. John Mann Ramin V. Parsey J. S. Dileep Kumar 《Bioorganic & medicinal chemistry》2013,21(17):5598-5604
The 5-HT1AR partial agonist PET radiotracer, [11C]CUMI-101, has advantages over an antagonist radiotracer as it binds preferentially to the high affinity state of the receptor and thereby provides more functionally meaningful information. The major drawback of C-11 tracers is the lack of cyclotron facility in many health care centers thereby limiting widespread clinical or research use. We identified the fluoroethyl derivative, 2-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione (FECUMI-101) (Ki = 0.1 nM; Emax = 77%; EC50 = 0.65 nM) as a partial agonist 5-HT1AR ligand of the parent ligand CUMI-101. FECUMI-101 is radiolabeled with F-18 by O-fluoroethylation of the corresponding desmethyl analogue (1) with [18F]fluoroethyltosylate in DMSO in the presence of 1.6 equiv of K2CO3 in 45 ± 5% yield (EOS). PET shows [18F]FECUMI-101 binds specifically to 5-HT1AR enriched brain regions of baboon. The specificity of [18F]FECUMI-101 binding to 5-HT1AR was confirmed by challenge studies with the known 5-HT1AR ligand WAY100635. These findings indicate that [18F]FECUMI-101 can be a viable agonist ligand for the in vivo quantification of high affinity 5-HT1AR with PET. 相似文献
5.
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
6.
A.M. Waszkielewicz A. Gunia N. Szkaradek K. Pytka A. Siwek G. Satała A.J. Bojarski E. Szneler H. Marona 《Bioorganic & medicinal chemistry letters》2013,23(15):4419-4423
A series of new xanthone derivatives with piperazine moiety [1–7] was synthesized and evaluated for their pharmacological properties. They were subject to binding assays for α1 and β1 adrenergic as well as 5-HT1A, 5-HT6 and 5-HT7b serotoninergic receptors. Five of the tested compounds were also evaluated for their anticonvulsant properties. The compound 3a 3-methoxy-5-{[4-(2-methoxyphenyl)piperazin-1-yl]methyl}-9H-xanthen-9-one hydrochloride exhibited significantly higher affinity for serotoninergic 5-HT1A receptors (Ki = 24 nM) than other substances. In terms of anticonvulsant activity, 6-methoxy-2-{[4-(benzyl)piperazin-1-yl]methyl}-9H-xanthen-9-one (5) proved best properties. Its ED50 determined in maximal electroshock (MES) seizure assay was 105 mg/kg b.w. (rats, p.o.). Combining of xanthone with piperazine moiety resulted in obtaining of compounds with increased bioavailability after oral administration. 相似文献
7.
Ferdinando Fiorino Beatrice Severino Francesca De Angelis Elisa Perissutti Elisa Magli Francesco Frecentese Antonella Esposito Paola Massarelli Cristina Nencini Vincenzo Santagada Giuseppe Caliendo 《Bioorganic & medicinal chemistry letters》2010,20(9):2978-2982
N′-Cyanoisonicotinamidine derivatives, linked to an arylpiperazine moiety, were prepared to identify highly selective and potent 5-HT1A ligands as potential pharmacological tools in studies of wide spread psychiatric disorders. The combination of structural elements (heterocyclic nucleus, alkyl chain and 4-substituted piperazine) known to be critical in order to have affinity on 5-HT1A receptor and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. In binding studies, several molecules showed affinity in nanomolar and subnanomolar range at 5-HT1A and moderate to no affinity for other relevant receptors (5-HT2A, 5-HT2C, D1, D2, α1 and α2). N′-Cyano-N-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)isonicotinamidine (4o) with Ki = 0.038 nM, was the most active and selective derivative for the 5-HT1A receptor with respect to other serotoninergic, dopaminergic and adrenergic receptors. 相似文献
8.
Enza Lacivita Pantaleo Di Pilato Madia Letizia Stama Nicola Antonio Colabufo Francesco Berardi Roberto Perrone Bianca De Filippis Giovanni Laviola Walter Adriani Mauro Niso Marcello Leopoldo 《Bioorganic & medicinal chemistry letters》2013,23(22):6083-6086
Here we report the synthesis, pharmacological and pharmacokinetic evaluation of a pilot set of compounds structurally related to the potent and selective 5-HT7 ligand LP-211. Among the studied compounds, N-pyridin-3-ylmethyl-3-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]ethoxy]propanamide (4b) showed high affinity for 5-HT7 receptors (Ki = 23.8 nM), selectivity over 5-HT1A receptors (>50-fold), in vitro metabolic stability (82%) and weak interaction with P-glycoprotein (BA/AB = 3.3). Compound 4b was injected ip in mice to preliminarily evaluate its distribution between blood and brain. 相似文献
9.
《Bioorganic & medicinal chemistry》2016,24(21):5462-5480
Multitarget approaches, i.e., addressing two or more targets simultaneously with a therapeutic agent, are hypothesized to offer additive therapeutic benefit for the treatment of neurodegenerative diseases. Validated targets for the treatment of Parkinson’s disease are, among others, the A2A adenosine receptor (AR) and the enzyme monoamine oxidase B (MAO-B). Additional blockade of brain A1 ARs may also be beneficial. We recently described 8-benzyl-substituted tetrahydropyrazino[2,1-f]purinediones as a new lead structure for the development of such multi-target drugs. We have now designed a new series of tetrahydropyrazino[2,1-f]purinediones to extensively explore their structure–activity-relationships. Several compounds blocked human and rat A1 and A2AARs at similar concentrations representing dual A1/A2A antagonists with high selectivity versus the other AR subtypes. Among the best dual A1/A2AAR antagonists were 8-(3-(4-chlorophenyl)propyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (41, Ki human A1: 65.5 nM, A2A: 230 nM; Ki rat A1: 352 nM, A2A: 316 nM) and 1,3-dimethyl-8-((2-(thiophen-2-yl)thiazol-4-yl)methyl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (57, Ki human A1: 642 nM, A2A: 203 nM; Ki rat A1: 166 nM, A2A: 121 nM). Compound 57 was found to be well water-soluble (0.7 mg/mL) at a physiological pH value of 7.4. One of the new compounds showed triple-target inhibition: (R)-1,3-dimethyl-8-(2,1,3,4-tetrahydronaphthalen-1-yl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (49) was about equipotent at A1 and A2AARs and at MAO-B (Ki human A1: 393 nM, human A2A: 595 nM, IC50 human MAO-B: 210 nM) thus allowing future in vivo explorations of the intended multi-target approach. 相似文献
10.
《Bioorganic & medicinal chemistry》2016,24(18):3994-4007
A series of novel 3β-aminotropane derivatives containing a 2-naphthalene or a 2-quinoline moiety was synthesised and evaluated for their affinity for 5-HT1A, 5-HT2A and D2 receptors. Their affinity for the receptors was in the nanomolar to micromolar range. p-Substitution (6c, 6f, 6i, 6l, 6o), as well as substitution with chlorine atoms (6g, 6h, 6i), led to a significant increase in binding affinity for D2 receptors with compounds 6f (Ki = 0.6 nM), 6c and 6i (Ki = 0.4 nM), having the highest binding affinities. m-Substituted derivatives were the most promising ligands in terms of 5-HT2A receptor binding affinity whereas 2-quinoline derivatives (10a, 10b) displayed the highest affinity for 5-HT1AR and were the most selective ligands with Ki = 62.7 nM and Ki = 30.5 nM, respectively. Finally, the selected ligands 6b, 6d, 6e, 6g, 6h, 6k, 6n and 6o, with triple binding activity for the D2, 5-HT1A and 5-HT2A receptors, were subjected to in vivo tests, such as those for induced hypothermia, climbing behaviour and the head twitch response, in order to determine their pharmacological profile. The tested ligands presented neither agonist nor antagonist properties for the 5-HT1A receptors in the induced hypothermia and lower lip retraction (LLR) tests. All tested compounds displayed antagonistic activity against 5-HT2A, with 6n and 6o being the most active. Four (6b, 6k, 6n and 6o) out of eight tested compounds could be classified as D2 antagonists. Additionally, evaluation of metabolic stability was performed for selected ligands, and introduction of halogen atoms into the benzene ring of 6h, 6k, 6n and 6o improved their metabolic stability. The project resulted in the selection of the lead compounds 6n and 6o, which had antipsychotic profiles, combining dopamine D2-receptor and 5-HT2A antagonism and metabolic stability. 相似文献
11.
《Bioorganic & medicinal chemistry》2014,22(15):4323-4337
We previously reported that the novel dual 5-HT2B and 5-HT7 receptor antagonist N-(9-hydroxy-9H-fluorene-2-carbonyl)guanidine (4) exerted a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs. To develop a synthetic strategy, we performed docking studies of lead compound 4 bound to 5-HT2B and 5-HT7 receptors, and observed that the carbonyl guanidine group forms a tight interaction network with an active center Asp (D135:5-HT2B, D162:5-HT7), Tyr (Y370:5-HT2B, Y374:5-HT7) and aromatic residue (W131:5-HT2B, F158:5-HT7). Based on molecular modeling results, we optimized the substituents at the 5- to 8-position and 9-position of the fluorene ring and identified N-(diaminomethylene)-9-hydroxy-9-methyl-9H-fluorene-2-carboxamide (24a) exhibits potent affinity for 5-HT2B (Ki = 4.3 nM) and 5-HT7 receptor (Ki = 4.3 nM) with high selectivity over 5-HT2A, 5-HT2C, α1, D2 and M1 receptors. Compound 24a reversed the hypothermic effect of 5-carboxamidotryptamine (5-CT) in mice and also showed a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs when orally administered at 30 mg/kg. Compound 24a is therefore a promising candidate for a novel class of anti-migraine agent without any adverse effects. 相似文献
12.
Ronald C. Bernotas Schuyler A. Antane Steven E. Lenicek Simon N. Haydar Albert J. Robichaud Boyd L. Harrison Guo Ming Zhang Deborah Smith Joseph Coupet Lee E. Schechter 《Bioorganic & medicinal chemistry letters》2009,19(24):6935-6938
1-(2-Aminoethyl)-3-(arylsulfonyl)-1H-pyrrolopyridines were prepared. Binding assays indicated they are 5-HT6 receptor ligands, among which 6f and 6g showed high affinity for 5-HT6 receptors with Ki = 3.9 and 1.7 nM, respectively. 相似文献
13.
Haifeng Sun Liyuan Zhu Huicui Yang Wangke Qian Lin Guo Shengbin Zhou Bo Gao Zeng Li Yu Zhou Hualiang Jiang Kaixian Chen Xuechu Zhen Hong Liu 《Bioorganic & medicinal chemistry》2013,21(4):856-868
An effective and rapid method for the microwave-assisted preparation of the key intermediate for the total synthesis of tetrahydroprotoberberines (THPBs) including l-stepholidine (l-SPD) was developed. Thirty-one THPB derivatives with diverse substituents on A and D ring were synthesized, and their binding affinity to dopamine D1, D2 and serotonin 5-HT1A and 5-HT2A receptors were determined. Compounds 18k and 18m were identified as partial agonists at the D1 receptor with Ki values of 50 and 6.3 nM, while both compounds act as D2 receptor antagonists (Ki = 305 and 145 nM, respectively) and 5-HT1A receptor full agonists (Ki = 149 and 908 nM, respectively). These two THPBs compounds exerted antipsychotic actions in animal models. Further electrophysiological studies employing single-unit recording in intact animals demonstrated that 18k-excited dopaminergic (DA) neurons are associated with its 5-HT1A receptor agonistic activity. These results suggest that these two compounds targeted to multiple neurotransmitter receptors may present novel lead drugs with new pharmacological profiles for the treatment of schizophrenia. 相似文献
14.
《Bioorganic & medicinal chemistry》2016,24(12):2794-2808
A new series of 7-aminopyrazolo[4,3-d]pyrimidine derivatives (1–31) were synthesized to evaluate some structural modifications at the 2- and 5-positions aimed at shifting affinity towards the human (h) A2A adenosine receptor (AR) or both hA2A and hA1 ARs. The most active compounds were those featured by a 2-furyl or 5-methylfuran-2-yl moiety at position 5, combined with a benzyl or a substituted-benzyl group at position 2. Several of these derivatives (22–31) displayed nanomolar affinity for the hA2A AR (Ki = 3.62–57 nM) and slightly lower for the hA1 ARs, thus showing different degrees (3–22 fold) of hA2A versus hA1 selectivity. In particular, the 2-(2-methoxybenzyl)-5-(5-methylfuran-2-yl) derivative 25 possessed the highest hA2A and hA1 AR affinities (Ki = 3.62 nM and 18 nM, respectively) and behaved as potent antagonist at both these receptors (cAMP assays). Its 2-(2-hydroxybenzyl) analog 26 also showed a high affinity for the hA2A AR (Ki = 5.26 nM) and was 22-fold selective versus the hA1 subtype. Molecular docking investigations performed at the hA2A AR crystal structure and at a homology model of the hA1 AR allowed us to represent the hypothetical binding mode of our derivatives and to rationalize the observed SARs. 相似文献
15.
Ronald C. Bernotas Schuyler Antane Rajesh Shenoy Van-Duc Le Ping Chen Boyd L. Harrison Albert J. Robichaud Guo Ming Zhang Deborah Smith Lee E. Schechter 《Bioorganic & medicinal chemistry letters》2010,20(5):1657-1660
Novel 3-(arylsulfonyl)-1-(azacyclyl)-1H-indoles 6 were synthesized as potential 5-HT6 receptor ligands, based on constraining a basic side chain as either a piperidine or a pyrrolidine. Many of these compounds had good 5-HT6 binding affinity with Ki values <10 nM. Depending on substitution, both agonists (e.g., 6o: EC50 = 60 nM, Emax = 70%) and antagonists (6y: IC50 = 17 nM, Imax = 86%) were identified in a 5-HT6 adenylyl cyclase assay. 相似文献
16.
《Bioorganic & medicinal chemistry》2014,22(21):6026-6038
A series of 9-disubstituted N-(9H-fluorene-2-carbonyl)guanidine derivatives have been discovered as potent and orally active dual 5-HT2B and 5-HT7 receptor antagonists. Upon screening several compounds, N-(diaminomethylene)-4′,5′-dihydro-3′H-spiro[fluorene-9,2′-furan]-2-carboxamide (17) exhibited potent affinity for both 5-HT2B (Ki = 5.1 nM) and 5-HT7 (Ki = 1.7 nM) receptors with high selectivity over 5-HT2A, 5-HT2C, α1, D2 and M1 receptors. Optical resolution of the intermediate carboxylic acid 16 via the formation of diastereomeric salts using chiral alkaloids gave the optically pure compounds (R)-17 and (S)-17. Both enantiomers suppressed 5-HT-induced dural protein extravasation in guinea pigs in a dose-dependent manner and the amount of leaked protein was suppressed to near normal levels when orally administrated at 10 mg/kg. (R)-17 and (S)-17 were therefore selected as candidates for human clinical trials. 相似文献
17.
Andreas Nievergelt Peter Huonker Roland Schoop Karl-Heinz Altmann Jürg Gertsch 《Bioorganic & medicinal chemistry》2010,18(9):3345-3351
Animal studies suggest that ginger (Zingiber officinale Roscoe) reduces anxiety. In this study, bioactivity-guided fractionation of a ginger extract identified nine compounds that interact with the human serotonin 5-HT1A receptor with significant to moderate binding affinities (Ki = 3–20 μΜ). [35S]-GTPγS assays indicated that 10-shogaol, 1-dehydro-6-gingerdione, and particularly the whole lipophilic ginger extract (Ki = 11.6 μg/ml) partially activate the 5-HT1A receptor (20–60% of maximal activation). In addition, the intestinal absorption of gingerols and shogaols was simulated and their interactions with P-glycoprotein were measured, suggesting a favourable pharmacokinetic profile for the 5-HT1A active compounds. 相似文献
18.
Chul Min Park So Young Kim Woo Kyu Park Jung Hwan Choi Churl Min Seong 《Bioorganic & medicinal chemistry letters》2010,20(17):5221-5224
(Piperazin-1-yl-phenyl)-arylsulfonamides were synthesized and identified to show high affinities for both 5-HT2C and 5-HT6 receptors. Among them, naphthalene-2-sulfonic acid isopropyl-[3-(4-methyl-piperazin-1-yl)-phenyl]-amide (6b) exhibits the highest affinity towards both 5-HT2C (IC50 = 4 nM) and 5-HT6 receptors (IC50 = 3 nM) with good selectivity over other serotonin (5-HT1A, 5-HT2A, and 5-HT7) and dopamine (D2–D4) receptor subtypes. In 5-HT2C and 5-HT6 receptor functional assays, this compound showed considerable antagonistic activity for both receptors. 相似文献
19.
Ermitas Alcalde Neus Mesquida Sara López-Pérez Jordi Frigola Ramon Mercè Jörg Holenz Marta Pujol Enrique Hernández 《Bioorganic & medicinal chemistry》2009,17(20):7387-7397
Further studies in quest of 5-HT6 serotonin receptor ligands led to the design and synthesis of a few selected examples of N-(inden-5-yl)sulfonamides with a ring-constrained aminoethyl side chain at the indene 3-position, some of which exhibited a high binding affinity, such as the pyrrolidine analogue 28 (Ki = 3 nM). Moreover, the structurally abbreviated N-(inden-5-yl)sulfonamides showed Ki values ?43 nM, which indicates that neither the N,N-aminoethyl nor the conformationally restricted aminoethyl side arm at the indene 3-position are required for binding. Selected compounds were then tested in a functional cAMP stimulation assay and found to act as 5-HT6 antagonists, although with moderate potency at the micromolar level. 相似文献
20.
Narsimha Reddy Penthala Purushothama Rao Ponugoti Justin R. Nickell Agripina G. Deaciuc Linda P. Dwoskin Peter A. Crooks 《Bioorganic & medicinal chemistry letters》2013,23(11):3342-3345
Central heterocyclic ring size reduction from piperidinyl to pyrrolidinyl in the vesicular monoamine transporter-2 (VMAT2) inhibitor GZ-793A and its analogs resulted in novel N-propane-1,2(R)-diol analogs 11a–i. These compounds were evaluated for their affinity for the dihydrotetrabenazine (DTBZ) binding site on VMAT2 and for their ability to inhibit vesicular dopamine (DA) uptake. The 4-difluoromethoxyphenethyl analog 11f was the most potent inhibitor of [3H]-DTBZ binding (Ki = 560 nM), with 15-fold greater affinity for this site than GZ-793A (Ki = 8.29 μM). Analog 11f also showed similar potency of inhibition of [3H]-DA uptake into vesicles (Ki = 45 nM) compared to that for GZ-793A (Ki = 29 nM). Thus, 11f represents a new water-soluble inhibitor of VMAT function. 相似文献