- Design and synthesis of new potent 5-HT7 receptor ligands as a candidate for the treatment of central nervous system diseases
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Owing to their multifunctional pharmacological profiles (including dual 5-HT1A/5-HT7 action), arylpiperazine derivatives are widely used for treating central nervous system diseases including the depression or neuropathic pain. Herein we describe the design, synthesis and evaluation of biological activity of novel 5-HT7 ligands derived of 2,4,6-triamino-1,3,5-triazine. The studied compounds showed affinity and high selectively towards 5-HT7 receptor with the two most active compounds 34 (Ki = 61 nM), 22 (Ki = 109 nM) showing good metabolic stability and moderate affinity to CYP3A4 isoenzyme. Compound 22 had high hepatotoxicity at a concentration below 50 μM, while compound 34 showed low hepatotoxicity even at a concentration above 50 μM.
- Drabczyk, Anna K.,Latacz, Gniewomir,Ja?kowska, Jolanta,Ku?aga, Damian,Pla?uk, Damian,Rózga, Karolina,Sata?a, Grzegorz
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supporting information
(2021/10/29)
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- Multitarget Compounds for Bipolar Disorder: From Rational Design to Preliminary Pharmacokinetic Evaluation
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Due to the complex and multifactorial nature of bipolar disorder (BD), single-target drugs have traditionally provided limited relief with no disease-modifying effects. In line with the polypharmacology paradigm, we attempted to overcome these limitations by devising two series of multitarget-directed ligands endowed with both a partial agonist profile at dopamine receptor D3 (D3R) and inhibitory activity against glycogen synthase kinase 3 beta (GSK-3β). These are two structurally unrelated targets that play independent, yet connected, roles in cognition and mood regulation. Two compounds (7 and 10) emerged as promising D3R/GSK-3β multitarget-directed ligands with nanomolar activity at D3R and low-micromolar inhibition of GSK-3β, thereby confirming, albeit preliminarily, the feasibility of our strategy. Furthermore, 7 showed promising drug-like properties in stability and pharmacokinetic studies.
- Di Martino, Rita Maria Concetta,Bottegoni, Giovanni,Seghetti, Francesca,Russo, Debora,Penna, Ilaria,De Simone, Alessio,Ottonello, Giuliana,Mandrup Bertozzi, Sine,Armirotti, Andrea,Bandiera, Tiziano,Belluti, Federica,Cavalli, Andrea
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supporting information
p. 949 - 954
(2020/05/04)
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- Design, synthesis, and evaluation of N-(4-(4-phenyl piperazin-1-yl)butyl)-4-(thiophen-3-yl)benzamides as selective dopamine D3 receptor ligands
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As part of our on-going effort to explore the role of dopamine receptors in drug addiction and identify potential novel therapies for this condition, we have a identified a series of N-(4-(4-phenyl piperazin-1-yl)butyl)-4-(thiophen-3-yl)benzamide D3 ligands. Members of this class are highly selective for D3 versus D2, and we have identified two compounds (13g and 13r) whose rat in vivo IV pharmacokinetic properties that indicate that they are suitable for assessment in in vivo efficacy models of substance use disorders.
- Chen, Peng-Jen,Taylor, Michelle,Griffin, Suzy A.,Amani, Armaghan,Hayatshahi, Hamed,Korzekwa, Kenneth,Ye, Min,Mach, Robert H.,Liu, Jin,Luedtke, Robert R.,Gordon, John C.,Blass, Benjamin E.
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supporting information
p. 2690 - 2694
(2019/08/07)
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- Compound with dopamine D3 receptor adjusting activity, and applications thereof
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The invention relates to a compound with dopamine D3 receptor adjusting activity, and applications thereof, and more specifically discloses dopamine receptor D3R as a novel target of post-traumatic stress disorder (PTSD) in prevention, treatment/or auxiliary treatment of PTSD, and screening of anti-PTSD medicines, and relates to applications of a compound with dopamine receptor D3R adjusting activity in preparation of medicines used for preventing, treatment and/or auxiliary treatment of PTSD.
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Paragraph 0191; 0195
(2019/03/22)
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- Design, synthesis, and evaluation of bitopic arylpiperazine-phthalimides as selective dopamine D3 receptor agonists
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The dopamine D3 receptor (D3R) is a proven therapeutic target for the treatment of neurological and neuropsychiatric disorders. In particular, D3R-selective ligands that can eliminate side effects associated with dopamine D2 receptor (D2R) therapeutics have been validated. However, the high homology in signaling pathways and the sequence similarity between D2R and D3R have rendered the development of D3R-selective ligands challenging. Herein, we designed and synthesized a series of piperazine-phthalimide bitopic ligands based on a fragment-based and molecular docking inspired design. Compound 9i was identified as the most selective D3R ligand among these bitopic ligands. Its selectivity was improved compared to reference compounds 1 and 2 by 9- and 2-fold, respectively, and it was 21-fold more potent than compound 2. Molecular docking demonstrated that the orientation of Leu2.64 and Phe7.39 and the packing at the junction of helices may affect the specificity for D3R over D2R. Functional evaluation revealed that D3R-selective ligand 9i displayed a subpicomolar agonist activity at D3R with a 199-fold increase in potency compared to quinpirole. These results may be useful for the fragment-based design of bitopic compounds as selective D3R ligands.
- Cao, Yongkai,Sun, Ningning,Zhang, Jiumei,Liu, Zhiguo,Tang, Yi-zhe,Wu, Zhengzhi,Kim, Kyeong-Man,Cheon, Seung Hoon
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p. 1457 - 1465
(2018/10/02)
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- Design, Synthesis, Structure-Activity Relationship Studies, and Three-Dimensional Quantitative Structure-Activity Relationship (3D-QSAR) Modeling of a Series of O-Biphenyl Carbamates as Dual Modulators of Dopamine D3 Receptor and Fatty Acid Amide Hydrolase
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We recently reported molecules designed according to the multitarget-directed ligand paradigm to exert combined activity at human fatty acid amide hydrolase (FAAH) and dopamine receptor subtype D3 (D3R). Both targets are relevant for tackling several types of addiction (most notably nicotine addiction) and other compulsive behaviors. Here, we report an SAR exploration of a series of biphenyl-N-[4-[4-(2,3-substituted-phenyl)piperazine-1-yl]alkyl]carbamates, a novel class of molecules that had shown promising activities at the FAAH-D3R target combination in preliminary studies. We have rationalized the structural features conducive to activities at the main targets and investigated activities at two off-targets: dopamine receptor subtype D2 and endocannabinoid receptor CB1. To understand the unexpected affinity for the CB1 receptor, we devised a 3D-QSAR model, which we then prospectively validated. Compound 33 was selected for PK studies because it displayed balanced affinities for the main targets and clear selectivity over the two off-targets. 33 has good stability and oral bioavailability and can cross the blood-brain barrier.
- De Simone, Alessio,Russo, Debora,Ruda, Gian Filippo,Micoli, Alessandra,Ferraro, Mariarosaria,Di Martino, Rita Maria Concetta,Ottonello, Giuliana,Summa, Maria,Armirotti, Andrea,Bandiera, Tiziano,Cavalli, Andrea,Bottegoni, Giovanni
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supporting information
p. 2287 - 2304
(2017/04/03)
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- Design, synthesis and evaluation of bitopic arylpiperazinephenyl-1,2,4-oxadiazoles as preferential dopamine D3 receptor ligands
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The dopamine D3 receptor (D3R) was proposed as a therapeutic target for drug development to treat drug abuse and addiction and neuropsychiatric disorders. Several D3R-selective modulators over the dopamine D2 receptor (D2R) can avoid extrapyramidal sympto
- Cao, Yongkai,Min, Chengchun,Acharya, Srijan,Kim, Kyeong-Man,Cheon, Seung Hoon
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p. 191 - 200
(2015/12/31)
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- High Affinity Dopamine D3 Receptor (D3R)-Selective Antagonists Attenuate Heroin Self-Administration in Wild-Type but not D3R Knockout Mice
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The dopamine D3 receptor (D3R) is a promising target for the development of pharmacotherapeutics to treat substance use disorders. Several D3R-selective antagonists are effective in animal models of drug abuse, especially
- Boateng, Comfort A.,Bakare, Oluyomi M.,Zhan, Jia,Banala, Ashwini K.,Burzynski, Caitlin,Pommier, Elie,Keck, Thomas M.,Donthamsetti, Prashant,Javitch, Jonathan A.,Rais, Rana,Slusher, Barbara S.,Xi, Zheng-Xiong,Newman, Amy Hauck
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p. 6195 - 6213
(2015/08/24)
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- PHENYL CARBAMATES AND THEIR USE AS INHIBITORS OF THE FATTY ACID AMIDE HYDROLASE (FAAH) ENZYME AND MODULATORS OF THE D3 DOPAMINE RECEPTOR (D3DR)
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The invention provides compounds of Formula (I) or pharmaceutically acceptable salts thereof wherein Ar', R1, R2, R3, R4, X, Y are as defined in the description of invention, as multi-target directed ligands (MT
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Page/Page column 33; 35; 36
(2015/02/02)
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- Synthesis and evaluation of fluoro substituted pyridinylcarboxamides and their phenylazo analogues for potential dopamine D3 receptor PET imaging
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A series of fluoro substituted pyridinylcarboxamides and their phenylazo analogues with high affinity and selectivity for the dopamine D3 receptor was synthesized by the use of 6-fluoropyridine-3-carbonyl chloride (1) and fluorophenylazocarboxylic ester (
- Nebel, Natascha,Maschauer, Simone,Bartuschat, Amelie L.,Fehler, Stefanie K.,Hübner, Harald,Gmeiner, Peter,Kuwert, Torsten,Heinrich, Markus R.,Prante, Olaf,Hocke, Carsten
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supporting information
p. 5399 - 5403
(2015/01/08)
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- Applying a multitarget rational drug design strategy: The first set of modulators with potent and balanced activity toward dopamine D3 receptor and fatty acid amide hydrolase
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Combining computer-assisted drug design and synthetic efforts, we generated compounds with potent and balanced activities toward both D3 dopamine receptor and fatty acid amide hydrolase (FAAH) enzyme. By concurrently modulating these targets, our compounds hold great potential toward exerting a disease-modifying effect on nicotine addiction and other forms of compulsive behavior.
- De Simone, Alessio,Ruda, Gian Filippo,Albani, Clara,Tarozzo, Glauco,Bandiera, Tiziano,Piomelli, Daniele,Cavalli, Andrea,Bottegoni, Giovanni
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supporting information
p. 4904 - 4907
(2014/05/06)
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- An interactive SAR approach to discover novel hybrid thieno probes as ligands for D2-like receptors with affinities in the subnanomolar range
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A series of [(phenylpiperazinyl)alkyl]-isoindole-1,3-dione derivatives was synthesized to serve as probes for dopaminergic receptors. Among this series, compound 6a showed the highest affinity towards D4 and D3 receptors with K i values in the low nanomolar range, and D2/D4- and D2/D3-selectivity indices of 72 and 20, respectively. Optimization rounds were adopted and led to the D4-selective ligand thiophene-2-carboxamide 9a with a Ki(D4) value of 0.62 nM, and to its butyl analog, 10a, with Ki(D4) and Ki(D3) values of 0.03 and 0.26 nM, respectively. Docking experiments revealed the importance of the unique D4 residue Arg186 in manipulating the ligands' D4-subtype-receptor selectivity. Copyright
- Abdel-Fattah, Mohamed A. O.,Lehmann, Jochen,Abadi, Ashraf H.
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p. 2247 - 2266
(2014/01/06)
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- Synthesis and biological evaluation of 2,4-diaminoquinazoline derivatives as novel heat shock protein 90 inhibitors
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Novel 2,4-diaminoquinazoline derivatives originating from a virtual screening approach were designed, synthesized and their biological activities as heat shock protein 90 (Hsp90) inhibitors were evaluated. The prepared compounds exhibited significant anti-proliferative activities against DU-145, HT-29, HCT-116, A375P and MCF-7 cancer cell lines. The selected compounds were tested against Her2, a client protein of Hsp90, and showed significant reduction in Her2 protein expression. Compound 6b was found the most potent, reduced Her2 protein expression levels and induced Hsp70 protein expression levels significantly.
- Thorat, Dhanaji Achyutrao,Doddareddy, Munikumar Reddy,Seo, Seon Hee,Hong, Tae-Joon,Cho, Yong Seo,Hahn, Ji-Sook,Pae, Ae Nim
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scheme or table
p. 1593 - 1597
(2011/05/05)
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- Arylpiperazine-containing pyrrole 3-carboxamide derivatives targeting serotonin 5-HT2A, 5-HT2C, and the serotonin transporter as a potential antidepressant
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Arylpiperzine-containing pyrrole 3-carboxamide derivatives were synthesized and evaluated as novel antidepressant compounds. The various analogues were efficiently prepared and bio-assayed for binding to 5-HT2A, 5-HT2C receptor, and
- Kang, Suk Youn,Park, Eun-Jung,Park, Woo-Kyu,Kim, Hyun Jung,Jeong, Daeyoung,Jung, Myung Eun,Song, Kwang-Seop,Lee, Suk Ho,Seo, Hee Jeong,Kim, Min Ju,Lee, MinWoo,Han, Ho-Kyun,Son, Eun-Jung,Pae, Ae Nim,Kim, Jeongmin,Lee, Jinhwa
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scheme or table
p. 1705 - 1711
(2010/06/19)
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- INDOLIZINE CARBOXAMIDES AND THE AZA AND DIAZA DERIVATIVES THEREOF
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The invention relates to neuroreceptor-active carboxamide-substituted indolizine derivatives of general formula (I) wherein X represents a group of general formula (X1).
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Page/Page column 54
(2010/10/19)
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- AZAINDOLE CARBOXAMIDES
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The invention relates to azaindole derivatives of general formula (I), wherein X represents a group of general formula (X1). Said compounds have a therapeutic potential in the treatment of diseases that are accompanied by an impaired dopamine metabolism a
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Page/Page column 32-33
(2010/11/30)
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- Synthesis and biological characterization of novel hybrid 7-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro- naphthalen-2-ol and their heterocyclic bioisosteric analogues for dopamine D2 and D3 receptors
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In a recent preliminary communication we described the development of a series of hybrid molecules for the dopamine D2 and D3 receptor subtypes. The design of these compounds was based on combining pharmacophoric elements of aminotetralin and piperazine m
- Dutta, Aloke K.,Venkataraman, Sylesh K.,Fei, Xiang-Shu,Kolhatkar, Rohit,Zhang, Shijun,Reith, Maarten E.A.
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p. 4361 - 4373
(2007/10/03)
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- N-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl, butenyl and butynyl}arylcarboxamides as novel dopamine D3 receptor antagonists
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The dopamine D3 receptor subtype has been targeted as a potential neurochemical modulator of the behavioral actions of psychomotor stimulants, such as cocaine. Previous synthetic studies provided structural requirements for high affinity bindin
- Newman, Amy Hauck,Cao, Jianjing,Bennett, Christina J.,Robarge, Michael J.,Freeman, Rebekah A.,Luedtke, Robert R.
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p. 2179 - 2183
(2007/10/03)
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- A novel series of hybrid compounds derived by combining 2-aminotetralin and piperazine fragments: Binding activity at D2 and D3 receptors
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A series of 7-hydroxy-2-[N-alkyl-(N-(4-phenylpiperazine)-alkyl)amino]tetralins was developed based on a novel hybrid approach that combined 2-aminotetralin and arylpiperazine pharmacophoric moieties. Our preliminary study revealed that a four-methylene bu
- Dutta, Aloke K,Fei, XiangShu,Reith, Maarten E.A
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p. 619 - 622
(2007/10/03)
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- Design and synthesis of [(2,3-dichlorophenyl)piperazin-1-yl]alkylfluorenylcarboxamides as novel ligands selective for the dopamine D3 receptor subtype
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The dopamine D3 receptor subtype has been recently targeted as a potential neurochemical modulator of the behavioral actions of psychomotor stimulants, such as cocaine. However, definitive behavioral investigations have been hampered by the lack of highly selective D3 agonists and antagonists. In an attempt to design a novel class of D3 ligands with which to study this receptor system, a series of chemically divergent compounds that possessed various structural features that exist within several classes of reputed D3 agents was screened and compared to the recently reported NGB 2904 (58b). On the basis of these results, a novel series of compounds was designed that included functional moieties that were required for high-affinity and selective binding to D3 receptors. All the compounds in this series included an aryl-substituted piperazine ring, a varying alkyl chain linker (C3-C5), and a terminal aryl amide. The compounds were synthesized and evaluated in vitro for binding in CHO cells transfected with human D2, D3, or D4 receptor cDNAs. D3 binding affinities ranged from Ki=1.4 to 1460 nM. The most potent analogue in this series, 51, demonstrated a D3/D2 selectivity of 64 and a D3/D4 selectivity of 1300. Structure-activity relationships for this class of ligands at D3 receptors will provide new leads toward the development of highly selective and potent molecular probes that will prove useful in the elucidation of the role D3 receptors play in the psychomotor stimulant and reinforcing properties of cocaine.
- Robarge,Husbands,Kieltyka,Brodbeck,Thurkauf,Newman
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p. 3175 - 3186
(2007/10/03)
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- NGB 2904 NGB 2849: Two highly selective dopamine D3 receptor antagonists
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N-(4-[4-{2, 3-dichlorophenyl}-1-piperazinyl]butyl(-3- fluorenylcarboxamide and N-(4-(4-{2,3-dichlorophenyl}-1-piperazinyl]butyl)- 2-biphenylenylcarboxamide were prepared in several steps from 2,3- dichloroaniline. These compounds were identified as highly selective dopamine D3 receptor antagonists.
- Yuan, Jun,Chen, Xi,Brodbeck, Robbin,Primus, Renee,Braun, Julia,Wasley, Jan W. F.,Thurkauf, Andrew
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p. 2715 - 2718
(2007/10/03)
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