13078-12-1Relevant articles and documents
Structure-Kinetic Profiling of Haloperidol Analogues at the Human Dopamine D2 Receptor
Fyfe, Tim J.,Kellam, Barrie,Sykes, David A.,Capuano, Ben,Scammells, Peter J.,Lane, J. Robert,Charlton, Steven J.,Mistry, Shailesh N.
supporting information, p. 9488 - 9520 (2019/11/11)
Haloperidol is a typical antipsychotic drug (APD) associated with an increased risk of extrapyramidal side effects (EPSs) and hyperprolactinemia relative to atypical APDs such as clozapine. Both drugs are dopamine D2 receptor (D2R) antagonists, with contrasting kinetic profiles. Haloperidol displays fast association/slow dissociation at the D2R, whereas clozapine exhibits relatively slow association/fast dissociation. Recently, we have provided evidence that slow dissociation from the D2R predicts hyperprolactinemia, whereas fast association predicts EPS. Unfortunately, clozapine can cause severe side effects independent of its D2R action. Our results suggest an optimal kinetic profile for D2R antagonist APDs that avoids EPS. To begin exploring this hypothesis, we conducted a structure-kinetic relationship study of haloperidol and revealed that subtle structural modifications dramatically change binding kinetic rate constants, affording compounds with a clozapine-like kinetic profile. Thus, optimization of these kinetic parameters may allow development of novel APDs based on the haloperidol scaffold with improved side-effect profiles.
Design, synthesis and docking study of 4-arylpiperazine carboxamides as monoamine neurotransmitters reuptake inhibitors
Paudel, Suresh,Sun, Ningning,Khadka, Daulat Bikram,Yoon, Goon,Kim, Kyeong-Man,Cheon, Seung Hoon
, p. 4127 - 4135 (2018/07/21)
Rational drug design method has been used to generate 4-arylpiperazine carboxamides in an effort to develop safer, more potent and effective monoamine neurotransmitters reuptake inhibitors. Out of twenty-seven synthesized compounds, compound 9 displayed potent monoamine neurotransmitter reuptake inhibitory activity against HEK cells transfected with hSERT or hNET. A Surflex-Dock docking model of 9 was also studied.
Design, synthesis, and systematic evaluation of 4-arylpiperazine- and 4-benzylpiperidine napthyl ethers as inhibitors of monoamine neurotransmitters reuptake
Paudel, Suresh,Min, Xiao,Acharya, Srijan,Khadka, Daulat Bikram,Yoon, Goon,Kim, Kyeong-Man,Cheon, Seung Hoon
, p. 5538 - 5546 (2018/10/09)
Two series of 4-arylpiperazine- and 4-benzylpiperidine naphthyl ethers were designed based on structure-activity relationship (SAR) and docking model of reported monoamine neurotransmitters reuptake inhibitors. The compounds were synthesized in 3-simple steps and their biological activities were evaluated. Several compounds were proven to be potent inhibitors of serotonin and norepinephrine reuptake. Computer docking was performed to study the interaction of the most potent compound 35 with human serotonin transporter. The results of the analyses suggest that 4-arylpiperazine- and 4-benzylpiperidine naphthyl ethers might be promising antidepressants worthy of further studies.
Design, synthesis, and biological evaluation of structurally constrained hybrid analogues containing ropinirole moiety as a novel class of potent and selective dopamine D3 receptor ligands
Zhou, Benhua,Hong, Kwon Ho,Ji, Min,Cai, Jin
, p. 1597 - 1609 (2018/07/31)
Two series of hybrid analogues were designed, synthesized, and evaluated as a novel class of selective ligands for the dopamine D3 receptor. Binding affinities of target compounds were determined (using the method of radioligand binding assay). Compared to comparator agent BP897, compounds 2a and 2c were found to demonstrate a considerable binding affinity and selectivity for D3 receptor, and especially compound 2h was similarly potent and more selective D3R ligand than BP897, a positive reference. Thus, they may provide valuable information for the discovery and development of highly potent dopamine D3 receptor ligands with outstanding selectivity.
Design, synthesis, and evaluation of bitopic arylpiperazine-phthalimides as selective dopamine D3 receptor agonists
Cao, Yongkai,Sun, Ningning,Zhang, Jiumei,Liu, Zhiguo,Tang, Yi-zhe,Wu, Zhengzhi,Kim, Kyeong-Man,Cheon, Seung Hoon
supporting information, p. 1457 - 1465 (2018/10/02)
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.
Design, synthesis and in vitro activity of 1,4-disubstituted piperazines and piperidines as triple reuptake inhibitors
Paudel, Suresh,Acharya, Srijan,Yoon, Goo,Kim, Kyeong-Man,Cheon, Seung Hoon
, p. 2266 - 2276 (2017/03/23)
Monoamine transporters regulate the concentration of monoamine neurotransmitters, which are essential for vital physiological processes, and their dysfunction can cause several central nervous system diseases. Monoamine transporters currently appear to be the potential target in the management of these disorders. In this study, homologation and bioisosterism techniques have been used in the designing of new 1,4-disubstituted piperazines and piperidines. These derivatives were synthesized and evaluated as potential triple reuptake inhibitors for studying the structure-activity relationships. The most advanced compound, 1-(4-(5-benzhydryl-1H-tetrazol-1-yl)butyl)-4-(3-phenylpropyl)piperazine (2i), was able to inhibit monoamine neurotransmitter reuptake in an in vitro test (IC50?=?158.7?nM for 5-HT, 99?nM for NE and 97.5?nM for DA). These novel potent triple reuptake inhibitor-based 1,4-disubstituted piperazine and piperidine scaffolds deserve further systematic optimization and pharmacological evaluation.
Exploration of substituted arylpiperazine–tetrazoles as promising dual norepinephrine and dopamine reuptake inhibitors
Paudel, Suresh,Acharya, Srijan,Yoon, Goo,Kim, Kyeong-Man,Cheon, Seung Hoon
, p. 5546 - 5555 (2016/10/22)
In the search for potent dual norepinephrine and dopamine reuptake inhibitors, several substituted arylpiperazine–tetrazoles were designed, synthesized and evaluated for their neurotransmitter reuptake inhibitory activities. Various derivatives exhibited selective and strong neurotransmitter reuptake inhibitory activity. In particular, compounds with a three-carbon linker displayed selective and stronger potency than those with two-carbon and four-carbon linkers. Interestingly, six compounds, 9b, 9c, 9d, 9o, 9q and 9u displayed more effective activity than the standard drug, bupropion. The provided SAR data and potent biological activity can offer useful guidelines for designing dual norepinephrine and dopamine reuptake inhibitors as effective therapeutic agents for treatment of several central nervous system diseases.
Design, synthesis, and biological evaluation of arylpiperazine-benzylpiperidines with dual serotonin and norepinephrine reuptake inhibitory activities
Paudel, Suresh,Acharya, Srijan,Kim, Kyeong-Man,Cheon, Seung Hoon
, p. 2137 - 2145 (2016/04/20)
The limitations of established serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) reuptake inhibitors necessitate the development of safer and more effective therapeutic agents. Based on the structures of 4-benzylpiperidine carboxamides and trazodone, arylpiperazine-benzylpiperidines with chemical scaffolds different from those of marketed drugs were designed, synthesized, and evaluated for their neurotransmitter reuptake inhibitory activities. The majority of the synthesized compounds showed greater NE than 5-HT reuptake inhibition. The activities were even greater than those of the standard drug, venlafaxine hydrochloride were. The derivatives with a three-carbon linker showed better activities than the derivatives with a two-carbon linker. Among the newly synthesized compounds, 2d exhibited the strongest reuptake inhibition of the neurotransmitters (IC50 = 0.38 μM for NE and 1.18 μM for 5-HT). The biological activity data demonstrate that arylpiperazine-benzylpiperidines have the potential to be developed as a new class of therapeutic agents to treat neuropsychiatric and neurodegenerative disorders.
An efficient scale up process for synthesis of N-arylpiperazines
Ravilla, Lokesh,Venkata Subba Naidu,Nagarajan, Kuppuswamy
supporting information, p. 4541 - 4544 (2015/06/30)
An efficient protocol for the synthesis of various substituted phenylpiperazines was developed using sulfolane as solvent. The protocol was clean, high yielding and products were obtained in high purities (≥99%). It was also fast and convenient, as the final products were precipitated as hydrochloride salts and could be obtained by filtration. Sulfolane, an aprotic, dipolar, high boiling and recoverable solvent was used as a substitute for common organic solvents.
Benzofuran derivatives, pharmaceutical composition containing the same, and a process for the preparation of the active ingredient
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, (2008/06/13)
The present invention is a piperazinylalkylbenzofuran derivative of the formula wherein R1 represents a C1-4 alkyl group, R2 stands for a hydrogen atom, X means an oxygen atom, Y is a hydroxyl group, Z represents a hydrogen atom, Ar′ represents a diphenylmethyl group, a pyridyl group, a partially saturated 5-membered heterocyclic group or a phenyl group, n has a value of 0 or 1, and pharmaceutically suitable acid addition salts thereof.
