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

5-HT1A and 5-HT7 receptors have been at the center of discussions recently due in part to their major role in the etiology of major central nervous system diseases such as depression, sleep disorders, and schizophrenia. As part of our search to identify dual targeting ligands for these receptors, we have carried out a systematic modification of a selective 5HT7 receptor ligand culminating in the identification of several dual 5-HT1A and 5-HT7 receptor ligands. Compound 16, a butyrophenone derivative of tetrahydroisoquinoline (THIQ), was identified as the most potent agent with low nanomolar binding affinities to both receptors. Interestingly, compound 16 also displayed moderate affinity to other clinically relevant dopamine receptors. Thus, it is anticipated that compound 16 may serve as a lead for further exploitation in our quest to identify new ligands with the potential to treat diseases of CNS origin.

show abstract

“…This has led to the suggestion and indeed demonstration that dual D 2 /D 3 receptor blockade produce effective antipsychotic actions. 35–37 …”

Section: Resultsmentioning

confidence: 99%

Design and synthesis of dual 5-HT1A and 5-HT7 receptor ligands

Ofori

Xiao-lin

Etukala

et al. 2016

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

show abstract

“…The multifunctional hybrid compounds D-519 and D-520, were derived from parent precursor molecules Pramipexole and 5-OHDPAT by a fragment based drug development approach4454. The rationale behind testing the parent precursor compounds was to evaluate whether these compounds exhibit an inherent modulation of α-syn aggregation property.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of alpha-synuclein aggregation by multifunctional dopamine agonists assessed by a novel in vitro assay and an in vivo Drosophila synucleinopathy model

Yedlapudi

Joshi

Luo

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Aggregation of alpha synuclein (α-syn) leading to dopaminergic neuronal death has been recognized as one of the main pathogenic factors in the initiation and progression of Parkinson’s disease (PD). Consequently, α-syn has been targeted for the development of therapeutics for PD. We have developed a novel assay to screen compounds with α-syn modulating properties by mimicking recent findings from in vivo animal studies involving intrastriatal administration of pre-formed fibrils in mice, resulting in increased α-syn pathology accompanying the formation of Lewy-body (LB) type inclusions. We found that in vitro generated α-syn pre-formed fibrils induce seeding of α-syn monomers to produce aggregates in a dose-and time-dependent manner under static conditions in vitro. These aggregates were toxic towards rat pheochromocytoma cells (PC12). Our novel multifunctional dopamine agonists D-519 and D-520 exhibited significant neuroprotection in this assay, while their parent molecules did not. The neuroprotective properties of our compounds were further evaluated in a Drosophila model of synucleinopathy. Both of our compounds showed protective properties in fly eyes against the toxicity caused by α-syn. Thus, our in vitro results on modulation of aggregation and toxicity of α-syn by our novel assay were further validated with the in vivo experiments.

show abstract

“…6–7, 24–32 The binding affinity for dopamine D2 and D3 receptors was determined by competitive radioligand-binding assays. The same general protocol was used to determine the inhibition constants for displacing [ 3 H]-spiroperidol binding to the cloned D2L and D3 receptors expressed in HEK cells.…”

Section: Methodsmentioning

confidence: 99%

“…Extensive structure-activity relationship (SAR) studies around previously identified lead molecules resulted in the development of potent and selective D3-prefering agonists/partial agonists. 6 Table 1 shows the chemical structures of few lead compounds along with their binding affinity and selectivity data for the D2/D3 receptors. Using these compounds, a 3-point pharmacophore hypothesis incorporating the directional features for the H-bond donor/acceptor functionalities was proposed.…”

Section: Introductionmentioning

confidence: 99%

Understanding the structural requirements of hybrid (S)-6-((2-(4-phenylpiperazin-1-yl)ethyl)(propyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol and its analogs as D2/D3 receptor ligands: a 3D QSAR investigation

Modi

Kharkar

et al. 2014

Med. Chem. Commun.

View full text Add to dashboard Cite

To gain insights into the structural requirements for dopamine D2 and D3 agonists in the treatment of Parkinson’s disease (PD) and to elucidate the basis of selectivity for D3 over D2 (D2/D3), 3D quantitative structure-activity relationship (3D QSAR) investigations using CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity indices analysis) methods were performed on a series of 45 structurally related D2 and D3 dopaminergic ligands. Two alignment methods (atom-based and flexible) and two charge calculation methods (Gasteiger-Hückel and AM1) were used in the present study. Overall, D2 affinity and selectivity (D2/D3) models performed better with r2cv values of 0.71 and 0.63 for CoMFA and 0.71 and 0.79 for CoMSIA, respectively. The corresponding predictive r2 values for the CoMFA and CoMSIA models were 0.92 and 0.86 and 0.91 and 0.78, respectively. The CoMFA models generated using flexible alignment outperformed the models with the atom-based alignment in terms of relevant statistics and interpretability of the generated contour maps while CoMSIA models obtained using atom-based alignment showed superiority in terms of internal and external predictive abilities. The presence of carbonyl group (C=O) attached to the piperazine ring and the hydrophobic biphenyl ring were found to be the most important features responsible for the D3 selectivity over D2. This study can be further utilized to design and develop selective and potent dopamine agonists to treat PD.

show abstract

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

Cited by 40 publications

References 34 publications

Design and synthesis of dual 5-HT1A and 5-HT7 receptor ligands

Design and synthesis of dual 5-HT1A and 5-HT7 receptor ligands

Inhibition of alpha-synuclein aggregation by multifunctional dopamine agonists assessed by a novel in vitro assay and an in vivo Drosophila synucleinopathy model

Understanding the structural requirements of hybrid (S)-6-((2-(4-phenylpiperazin-1-yl)ethyl)(propyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol and its analogs as D2/D3 receptor ligands: a 3D QSAR investigation

Contact Info

Product

Resources

About