共查询到20条相似文献,搜索用时 15 毫秒
1.
《Bioorganic & medicinal chemistry》2020,28(2):115245
Thiophene bioisosteres of potent GluN2B receptor negative allosteric modulators were prepared and evaluated pharmacologically. The five-step synthesis of 4,5,7,8-tetrahydro[7]annuleno[b]thiophen-6-one (10) was considerably improved by carboxylation of thiophene-3-carboxylic acid (8) in the first reaction step. Reductive amination and alkylation led to three homologous series of secondary and tertiary phenylalkylamines 5, 11 and 12. Metalation, reaction with 1-formylpiperidine and subsequent reduction provided hydroxymethyl derivatives 15 and 16, which had been designed as bioisosteres of phenols. 2-Bromo derivatives 18 were obtained by bromination of ketone 10 with NBS and subsequent reductive amination. High GluN2B affinity was achieved with [7]annuleno[b]thiophenes bearing a 3-phenylpropylamino or 4-phenylbutylamino moiety (e.g. 5c: Ki = 5.9 nM; 11d: Ki = 9.0 nM). Tertiary ethylamines 12 showed lower GluN2B affinity than tertiary methylamines 11 or secondary amines 5 (e.g. 5c: Ki = 5.9 nM; 11c: Ki = 6.0; 12c: Ki = 51 nM). A Br-atom or a hydroxymethyl moiety in 2-position were less tolerated by the GluN2B receptor. Very similar relationships between the structure and GluN2B affinity and structure and σ affinity, in particular σ2 affinity, were detected. A slight preference for the ifenprodil binding site of GluN2B receptors over σ1 and σ2 receptors was found for methylamines 11c (≈2-fold) and 11d (≈1.5–2-fold) as well as for bromo derivative 18c (≈3-fold). 相似文献
2.
《Bioorganic & medicinal chemistry》2014,22(23):6638-6646
Due to their beneficial side effect profile, NMDA receptor antagonists interacting selectively with the allosteric ifenprodil binding site of the GluN2B subunit are of major interest for the treatment of neurological and neurodegenerative disorders. A series of benzo[7]annulen-7-amines 6 was designed by conformational restriction of ifenprodil (1). At first the benzo[7]annulen-7-one 11 was prepared in a three-step synthesis comprising of a double Knoevenagel condensation of phthalaldehyde (7) with dimethyl 3-oxoglutarate (8), hydrogenation of 9 and saponification/decarboxylation of 10. Reductive amination of the ketone 11 with primary amines and NaBH(OAc)3 led to the secondary amines 6a–d, cis-6h and trans-6i. The tertiary amines 6e–g were obtained by SN2-substitution of the nosylate 13. Although H-bond forming substituents in 2- and 5-position are missing, the amines 6 exhibit high affinity towards GluN2B containing NMDA receptors. A distance of four to five bond lengths between the basic amino moiety and the phenyl ring in the side chain appears to be optimal for high GluN2B affinity. The phenylcyclohexylamine cis-6h and the 4-benzylpiperidine 6g show the highest GluN2B affinities (Ki = 2.3 nM and 2.9 nM, respectively). With respect to selectivity against the PCP binding site, σ1 and σ2 receptors the phenylpiperazine 6f is the most promising GluN2B antagonist. 相似文献
3.
《Bioorganic & medicinal chemistry》2014,22(1):393-397
Following previous studies focused on the search for new molecules targeting GluN2B-containing NMDA, a small series of 1-(1H-indol-3-yl)-2-(4-phenylpiperidin-1-yl)ethanone derivatives has been synthesized by using Microwave Assisted Organic Synthesis (MAOS). Given that GluN2B ligands frequently exert off-target effects we also tested their affinity towards sigma receptors. Binding assay revealed that only the 1-(5-hydroxy-1H-indol-3-yl)-2-(4-phenylpiperidin-1-yl)ethanone (7a) retained GluN2B affinity. Interestingly, the 5-methoxyindoles 5a and 6a were efficient and selective ligands toward σ2 receptor (Ki values of 10 nM and 20 nM, respectively). Thus, in this case the discovery of new σ2 receptor selective ligands was an unexpected result emerging from the screening of cross-activity against other CNS receptors. 相似文献
4.
The NMDA receptor containing GluN2B subunits represents a promising target for the development of drugs for the treatment of various neurological disorders including neurodegenerative diseases. In order to study the role of CH3 and OH moieties trisubstituted tetrahydro-3-benzazepines 4 were designed as missing link between tetra- and disubstituted 3-benzazepines 2 and 5. The synthesis of 4 comprises eight reaction steps starting from alanine. The intramolecular Friedel-Crafts acylation to obtain the ketone 12 and the base-catalyzed elimination of trifluoromethanesulfinate (CF3SO2?) followed by NaBH4 reduction represent the key steps. The GluN2B affinity of the cis-configured 3-benzazepin-1-ol cis-4a with a 4-phenylbutyl side chain (Ki?=?252?nM) is considerably lower than the GluN2B affinity of (R,R)-2 (Ki?=?17?nM) indicating the importance of the phenolic OH moiety for the interaction with the receptor protein. Introduction of an additional CH3 moiety in 2-position led to a slight decrease of GluN2B affinity as can be seen by comparing the affinity data of cis-4a and 5. The homologous phenylpentyl derivative cis-4b shows the highest GluN2B affinity (Ki?=?56?nM) of this series of compounds. According to docking studies cis-4a adopts the same binding mode as the cocrystallized ligand ifenprodil-keto 1A and 5 at the interface of the GluN2B and GluN1a subunits. The same crucial H-bonds are formed between the C(O)NH2 moiety of Gln110 within the GluN2B subunit and the protonated amino moiety and the OH moiety of (R,R)-cis-4a. 相似文献
5.
Ashutosh Banerjee Dirk Schepmann Bernhard Wünsch 《Bioorganic & medicinal chemistry》2010,18(11):4095-4102
A series of dioxadrol analogues with fluorine substituents in position 4 of the piperidine ring has been synthesized and pharmacologically evaluated. The key step in the synthesis was the fluorination of diastereomeric piperidones 6a and 6c as well as diastereomeric alcohols 9a and 9c with DAST. The reaction of the alcohols 9a and 9c took place with inversion of configuration. After removal of the Cbz-protective group, the NMDA receptor affinities of the resulting secondary amines 8a, 8c, 12b, and 12d were investigated in receptor binding studies. It was shown that the like-configuration of the ring junction was crucial for high NMDA receptor affinity. An axially oriented fluorine atom in position 4 led to 2-(2,2-diphenyl-1,3-dioxolan-4-yl)-4-fluoropiperidine (12d, WMS-2517) with a Ki-value of 27 nM. The NMDA receptor affinity of 8c (WMS-2513) with an additional fluorine atom in equatorial 4-position was slightly reduced (Ki = 81 nM). Both fluorinated dioxadrol derivatives 8c and 12d showed high selectivity against σ1 and σ2 receptors as well as the polyamine binding site of NR2B receptors. 相似文献
6.
《Bioorganic & medicinal chemistry》2019,27(23):115146
In this study, the impact of one or two hydroxy moieties at the benzo[7]annulene scaffold on the GluN2B affinity and cytoprotective activity was analyzed. The key intermediate for the synthesis of OH-substituted benzo[7]annulenamines 11–13 and 17 was the epoxyketone 8. Reductive epoxide opening of 8 resulted with high regioselectivity in the 5-hydroxyketone 9 (Pd(OAc)2, HCO2H, phosphane ligand) or the 6-hydroxyketone 10 (H2, Pd/C), whereas hydrolysis in aqueous dioxane led to the dihydroxyketone 14. Reductive amination of these ketones with primary amines and NaBH(OAc)3 afforded the benzo[7]annulenamines 11–13 and 17. In receptor binding studies 5-OH derivatives 11 and 12 showed higher GluN2B affinity than 6-OH derivatives 13, which in turn were more active than 5,6-di-OH derivative 17a. The same order was found for the cytoprotective activity of the ligands. The tertiary amine 12a with one OH moiety in 5-position represents the most promising GluN2B negative allosteric modulator with a binding affinity of Ki = 49 nM and a cytoprotective activity of IC50 = 580 nM. In the binding pocket 12a shows a crucial H-bond between the benzylic OH moiety and the backbone carbonyl O-atom of Ser132 (GluN1b). It was concluded that a 5-OH moiety is essential for the inhibition of the NMDA receptor associated ion channel, whereas a OH moiety in 6-position is detrimental for binding and inhibition. An OH or CH2OH moiety at 2-position results in binding at the ifenprodil binding site, but very weak ion channel inhibition. 相似文献
7.
Elena Sguazzini Hayden R. Schmidt Kavita A. Iyer Andrew C. Kruse Małgorzata Dukat 《Bioorganic & medicinal chemistry letters》2017,27(13):2912-2919
Fenpropimorph (1) is considered a “super high-affinity” σ1 receptor ligand (Ki = 0.005 nM for guinea pig σ1 receptors). Here, we examine the binding of 1 and several of its deconstructed analogs at human σ1 (hσ1) receptors. We monitored their subtype selectivity by determining the binding affinity at σ2 receptors. In addition, we validated an existing pharmacophore model at the molecular level by conducting 3D molecular modeling studies, using the crystal structure of hσ1 receptors, and Hydrophatic INTeractions (HINT) analysis. Our structure affinity relationship studies showed that 1 binds with lower affinity at hσ1 receptors (Ki = 17.3 nM) compared to guinea pig; moreover, we found that none of the fenpropimorph methyl groups is important for its binding at hσ1 receptors, nor is stereochemistry. For example, removal of all methyl groups as seen in 4 resulted in an almost 5-fold higher affinity at hσ1 receptors compared to 1 and 350-fold selectivity versus σ2 receptors. In addition, although the O atom of the morpholine ring does not contribute to affinity at hσ1 receptors (and might even detract from it), it plays role in subtype (σ1 versus σ2 receptor) selectivity. 相似文献
8.
Three series of bitobic arylpiperazine-phenyl-hexahydropyrazinoquino- lines analogues were designed, synthesizedand evaluated as a novel class of selective ligands for the dopamine D3 receptor. Compounds 15a (Ki of 11.7 ± 1.8 and 373 nM at D3 and D2, respectively), 15c (Ki of 5.49 and 264 nM at D3 and D2, respectively), 15e (Ki of 14.9 and 325 nM at D3 and D2, respectively), 15i (Ki of 13.8 and 401 nM at D3 and D2, respectively) and 15l (Ki of 13.6 and 870 nM at D3 and D2, respectively) were found to demonstrate good binding affinity and selectivity, and especially compound 15c showeda similar binding affinity and selectivity compared with the contrast drug BP897. 相似文献
9.
《Bioorganic & medicinal chemistry》2014,22(13):3316-3324
Desymmetrization of the pseudochiral (2r)-configured cyclohexane-1,2,3-triamines 8 with dimethyl oxalate led to racemic aminoquinoxaline-2,3-diones 9. Selective introduction of the κ pharmacophoric structural elements pyrrolidine and 3,4-dichlorophenylacetamide with a two-carbon distance afforded conformationally restricted κ agonists 13–15 based on the quinoxaline ring system. In competitive radioligand receptor binding studies the benzylamine 13b, the secondary amine 14b, and the carbamate 15 displayed high κ receptor affinity. The Ki value of the lead compound derived methoxycarbonyl derivative 15 is 9.7 nM. However, the κ affinity of 15 is exceeded by 13b and 14b with a basic functional group instead of the methoxycarbonyl group in 1-position of the quinoxaline system. The chlorine atoms of the dichlorophenylacetyl residue are essential, since the corresponding phenylacetyl analogs show considerably reduced κ affinity. The potent κ ligands 13b, 14b and 15 are selective over the related μ- and δ-opioid receptors, σ1, σ2 and NMDA receptors. In the [35S]GTPγS-binding assay 13b behaved as partial agonist with lower activity than U-69,593. 相似文献
10.
Rohit Bhat James A. Fishback Rae R. Matsumoto Jacques H. Poupaert Christopher R. McCurdy 《Bioorganic & medicinal chemistry letters》2013,23(17):5011-5013
Herein we report the SAR study which involved structural modifications to the linker length, aryl substitution and alkylamine ring size of the benzo[d]thiazol-2(3H)one based sigma receptor (σ) ligands. Many compounds in this series displayed low nanomolar affinity for the σ receptor subtypes. In particular, 8a showed high affinity (σ-1 Ki = 4.5 nM) for σ-1 receptors and moderately high selectivity (483-fold) over σ-2 receptors. 相似文献
11.
Abdol R. Hajipour Dominique Fontanilla Uyen B. Chu Marty Arbabian Arnold E. Ruoho 《Bioorganic & medicinal chemistry》2010,18(12):4397-4404
The sigma-1 receptor is a unique non-opioid, non-PCP binding site that has been implicated in many different pathophysiological conditions including psychosis, drug addiction, retinal degeneration and cancer. Based on the structure of fenpropimorph, a high affinity (Ki = 0.005 nM)1 sigma-1 receptor ligand and strong inhibitor of the yeast sterol isomerase (ERG2), we previously deduced a basic sigma-1 receptor pharmacophore or chemical backbone composed of a phenyl ring attached to a di-substituted nitrogen atom via an alkyl chain.2 Here, we report the design and synthesis of various N,N-dialkyl or N-alkyl-N-aralkyl derivatives based on this pharmacophore as well as their binding affinities to the sigma-1 receptor. We introduce three high affinity sigma-1 receptor compounds, N,N-dibutyl-3-(4-fluorophenyl)propylamine (9), N,N-dibutyl-3-(4-nitrophenyl)propylamine (3), and N-propyl-N′-4-aminophenylethyl-3-(4-nitrophenyl)propylamine (20) with Ki values of 17.7 nM, 0.36 nM, and 6 nM, respectively. In addition to sigma receptor affinity, we show through cytotoxicity assays that growth inhibition of various tumor cell lines occurs with our high affinity N,N-dialkyl or N-alkyl-N-aralkyl derivatives. 相似文献
12.
《Bioorganic & medicinal chemistry letters》2014,24(4):1021-1025
We describe here the synthesis and the binding interaction with σ1 and σ2 receptors of a series of new arylcarboxamide derivatives variously substituted on the aromatic portions. Maintaining a partial scaffold of a series of compounds previously synthesized by us, we evaluate the effect of the substitution on σ binding. The synthesized compounds have been tested to estimate their affinity and selectivity toward σ1 and σ2 receptors. Two out of 16 derivatives showed an interesting σ1 affinity (21.2 and 13.6 nM—compounds 2m and 2p) and a good selectivity (Ki(σ2)/Ki(σ1) >140 and >40, respectively). 相似文献
13.
In this work, an enlarged series of 1,2,4-triazolo[4,3-a]pyrazin-3-ones was designed to target the human (h) A2A adenosine receptor (AR) or both hA1 and hA2A ARs. The novel 8-amino-1,2,4-triazolopyrazin-3-one derivatives 1–25 featured a phenyl or a benzyl pendant at position 2 while different aryl/heteroaryl substituents were placed at position 6. Two compounds (8 and 10) endowed with high affinity (Ki = 7.2 and 10.6 nM) and a complete selectivity for the hA2A AR were identified. Moreover, several derivatives possessed nanomolar affinity for both hA1 and hA2A ARs (both Ki < 20 nM) and different degrees of selectivity versus the hA3 AR. Two selected compounds (10 and 25) demonstrated ability in preventing β-amyloid peptide (25–35)-induced neurotoxicity in SH-SY5Y cells. Results of docking studies at the hA2A and hA1 AR crystal structures helped us to rationalize the observed affinity data and to highlight that the steric hindrance of the substituents at the 2- and 6-position of the bicyclic core affects the binding mode in the receptor cavity. 相似文献
14.
Kazuma Ogawa Ryohei Masuda Kenji Mishiro Mengfei Wang Takashi Kozaka Kazuhiro Shiba Seigo Kinuya Akira Odani 《Bioorganic & medicinal chemistry》2019,27(10):1990-1996
Sigma-1 receptor imaging probes for determining the expression levels are desirable for diagnoses of various diseases and companion diagnoses of therapeutic agents targeting the sigma-1 receptor. In this study, we aimed to develop probes with higher affinity for the sigma-1 receptor. For this purpose, we synthesized and evaluated compounds, namely, vesamicol derivatives, in which alkyl chains of varying chain length were introduced between a piperazine ring and a benzene ring. The binding affinity of the vesamicol derivatives for the sigma-1 receptor tended to increase depending on the length of the alkyl chain between the benzene ring and the piperazine ring. The sigma-1 receptor of 2-(4-(3-phenylpropyl)piperazin-1-yl)cyclohexan-1-ol (5) (Ki?=?5.8?nM) exhibited the highest binding affinity; therefore, we introduced radioiodine into the benzene ring in 5. The radioiodine labeled probe [125I]2-(4-(3-(4-iodophenyl)propyl)piperazin-1-yl)cyclohexan-1-ol ([125I]10) showed high accumulation in the sigma-1 receptor expressing DU-145 cells both in vitro and in vivo. Co-injection of [125I]10 with an excess level of a sigma receptor ligand, haloperidol, resulted in a significant decrease in the tumor accumulation in vitro and in vivo, indicating sigma receptor-mediated tumor uptake. These results provide useful information for developing sigma-1 receptor imaging probes. 相似文献
15.
Corinna Lueg Dirk Schepmann Robert Günther Peter Brust Bernhard Wünsch 《Bioorganic & medicinal chemistry》2013,21(23):7481-7498
A convergent strategy was followed to modify systematically carbazole based CB2 receptor ligands. The length of the N-(fluoroalkyl) group (n in 7), the length of the alkanamide (m in 7) and the substitution pattern of the phenyl moiety (X and Y in 7) were varied systematically. The highest CB2 affinity was found for the 2-fluoroethyl substituted carbazole derivative 20a (Ki = 5.8 nM) containing the propionamide and the 2-bromo-4-fluorophenyl moiety. According to docking studies 20a fits nicely into the binding pocket of the CB2 receptor, but elongation of the fluoroethyl side chain leads to a different binding mode of the ligands. The high CB2 affinity together with the high selectivity over the CB2 subtype qualifies the fluoroethyl derivative 20a to be developed as a PET tracer. 相似文献
16.
《Bioorganic & medicinal chemistry letters》2014,24(6):1550-1556
A series of four novel analogues of DPA-714, bearing a fluoroalkynyl side chain (with a length ranging from three to six carbon atoms) in replacement of the fluoroethoxy motif, have been synthetized in six steps from commercially available methyl 4-iodobenzoate. The synthetic strategy for the preparation of these N,N-diethyl-2-(2-(4-(ω-fluoroalk-1-ynyl)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamides (7a–d) consisted in derivatizing a key iodinated building block featuring the pyrazolopyrimidine acetamide backbone of DPA-714, by Sonogashira couplings with various alkynyl reagents. The resulting alkynols were subsequently fluorinated, yielding the expected target derivatives. All four analogues exhibited slightly higher affinity and selectivity towards the TSPO 18 kDa (Ki vs [3H]PK11195: 0.35–0.79 nM; Ki vs [3H]flunitrazepam: >1000 nM) when compared to DPA-714 (Ki vs [3H]PK11195: 0.91 nM; Ki vs [3H]flunitrazepam: >1000 nM). Lipophilicities (HPLC, log D7.4) increased with the chain length (from 3.6 to 4.3) and were significantly higher than the one determined for DPA-714 (2.9). Preliminary in vitro metabolism evaluation using rat microsomal incubations and LC–MS analyses showed, for all four novel analogues, the absence of defluorinated metabolites. Among them, the fluoropentynyl compound, DPA-C5yne (7c), was selected, labelled in one single step with fluorine-18 from the corresponding tosylate and in vivo evaluated with PET on our in-house-developed rat model of acute local neuroinflammation. 相似文献
17.
《Bioorganic & medicinal chemistry》2016,24(18):4045-4055
The Oxa-Pictet–Spengler reaction of methyl 3-hydroxy-4-phenylbutanoate (8) was explored to obtain novel σ receptor ligands. 1-Acyl protected piperidone ketals 10 and 11 reacted with phenylethanol 8 to yield spirocyclic compounds. Aliphatic aldehyde acetals 19 provided 1,3-disubstituted 2-benzopyrans 20 with high cis-diastereoselectivity. The intramolecular Oxa-Pictet–Spengler reaction of 24 led to the tricyclic compound 25. The spirocyclic compounds 18 show high σ1 affinity (Ki 20–26 nM) and σ1/σ2 selectivity (>9-fold), when a large substituent (n-octyl, benzyl, phenylpropyl) is attached to the piperidine N-atom. Opening of the piperidine ring to yield aminoethyl (22, 23) or aminomethyl derivatives (21) resulted in reduced σ1 affinity and σ1/σ2 selectivity. 相似文献
18.
《Bioorganic & medicinal chemistry》2020,28(22):115726
Stereoisomeric 2-aryl-2-fluoro-cyclopropan-1-amines have been discovered as a new class of σ receptor ligands showing different selectivity for the two subtypes of the receptor. Generally, compounds substituted in 4-position are much more active than corresponding 3-substituted isomers. trans-2-Fluoro-2-(4-methoxyphenyl)cyclopropan-1-amine (19a) was the most potent (Ki = 4.8 nM) σ1 receptor ligand, while cis-2-fluoro-2-(4-trifluoromethylphenyl)cyclopropan-1-amine (20b) was the most potent (Ki = 95 nM) σ2 receptor ligand. 相似文献
19.
Prabhakar R. Polepally Kate White Eyal Vardy Bryan L. Roth Daneel Ferreira Jordan K. Zjawiony 《Bioorganic & medicinal chemistry letters》2013,23(10):2860-2862
Salvinorin A, the active ingredient of the hallucinogenic plant Salvia divinorum is the most potent known naturally occurring hallucinogen and is a selective κ-opioid receptor agonist. To better understand the ligand–receptor interactions, a series of dicarboxylic ester-type of salvinorin A derivatives were synthesized and evaluated for their binding affinity at κ-, δ- and μ-opioid receptors. Most of the analogues show high affinity to the κ-opioid receptor. Methyl malonyl derivative 4 shows the highest binding affinity (Ki = 2 nM), analogues 5, 7, and 14 exhibit significant affinity for the κ-receptor (Ki = 21, 36 and 39 nM). 相似文献
20.
Dennis A. Brown Manoj Mishra Suhong Zhang Swati Biswas Ingrid Parrington Tamara Antonio Maarten E.A. Reith Aloke K. Dutta 《Bioorganic & medicinal chemistry》2009,17(11):3923-3933
Here we report on the design and synthesis of several heterocyclic analogues belonging to the 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol series of molecules. Compounds were subjected to [3H]spiperone binding assays, carried out with HEK-293 cells expressing either D2 or D3 dopamine receptors, in order to evaluate their inhibition constant (Ki) at these receptors. Results indicate that N-substitution on the piperazine ring can accommodate various substituted indole rings. The results also show that in order to maintain high affinity and selectivity for the D3 receptor the heterocyclic ring does not need to be connected directly to the piperazine ring as the majority of compounds included here are linked either via an amide or a methylene linker to the heterocyclic moiety. The enantiomers of the most potent racemic compound 10e exhibited differential activity with (?)-10e (Ki; D2 = 47.5 nM, D3 = 0.57 nM) displaying higher affinity at both D2 and D3 receptors compared to its enantiomer (+)-10e (Ki; D2 = 113 nM, D3 = 3.73 nM). Additionally, compound (?)-10e was more potent and selective for the D3 receptor compared to either 7-OH-DPAT or 5-OH-DPAT. Among the bioisosteric derivatives, the indazole derivative 10g and benzo[b]thiophene derivative 10i exhibited the highest affinity for D2 and D3 receptors. In the functional GTPγS binding study, one of the lead molecules, (?)-15, exhibited potent agonist activity at both D2 and D3 receptors with preferential affinity at D3. 相似文献