Bioisosteric Heterocyclic Versions of 7-{[2-(4-Phenyl-piperazin-1-yl)ethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-ol: Identification of Highly Potent and Selective Agonists for Dopamine D3 Receptor with Potent in Vivo Activity

Biswas, Swati; Hazeldine, Stuart; Ghosh, Balaram; Parrington, Ingrid; Kuzhikandathil, Eldo V.; Reith, Maarten E. A.; Dutta, Aloke K.

doi:10.1021/jm701524h

Cited by 47 publications

(79 citation statements)

References 49 publications

(95 reference statements)

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“…In our recent publications, we have shown that newly developed D2/D3 agonists may act as both symptomatic and neuroprotective agents for the treatment of PD (Biswas et al 2008, Li et al 2010, Gogoi et al 2011). In this regard, we have recently characterized the neuroprotective effects of two lead compounds, D-512 and D-440, via assessment of their effects on neurotoxicity associated with 6-OHDA and MPP + administration in DAergic MN9D cells (Santra et al 2013).…”

Section: Discussionmentioning

confidence: 99%

The high‐affinity D2/D3 agonist D512 protects PC12 cells from 6‐OHDA‐induced apoptotic cell death and rescues dopaminergic neurons in the MPTP mouse model of Parkinson's disease

Shah

Rajagopalan

et al. 2014

Journal of Neurochemistry

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In this study, in vitro and in vivo experiments were carried out with the high-affinity multifunctional D2/D3 agonist D-512 in order to explore its potential neuroprotective effects in models of Parkinson’s disease (PD) and the potential mechanism(s) underlying such properties. Pretreatment with D-512 in vitro was found to rescue rat adrenal phaeochromocytoma PC12 cells from toxicity induced by 6-hydroxydopamine (6-OHDA) administration in a dose-dependent manner. Neuroprotection was found to coincide with reductions in intracellular reactive oxygen species, lipid peroxidation, and DNA damage. In vivo, pretreatment with 0.5 mg/kg D-512 was protective against neurodegenerative phenotypes associated with systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), including losses in striatal dopamine (DA), reductions in numbers of DAergic neurons in the substantia nigra (SN), and locomotor dysfunction. These observations strongly suggest that the multifunctional drug D-512 may constitute a novel viable therapy for PD.

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Section: Discussionmentioning

confidence: 99%

The high‐affinity D2/D3 agonist D512 protects PC12 cells from 6‐OHDA‐induced apoptotic cell death and rescues dopaminergic neurons in the MPTP mouse model of Parkinson's disease

Shah

Rajagopalan

et al. 2014

Journal of Neurochemistry

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“…Compounds D-264 and D301 were synthesized by us as described previously ([18], in which compound 24c is D-301, and [19], in which compound (−)-34 is D-264). Plasmid DNA (pcDNA3.1) expressing human G o1 was obtained from the cDNA Resource Center (www.cdna.org).…”

Section: Methodsmentioning

confidence: 99%

“…These compounds are two related hybrid tetrahydrobenzo[d]thiazole based arylpiperazines developed in our earlier work [18,19]: D-264 and D-301. Both compounds contain the tetrahydrobenzo[d]thiazole moiety, connected through a (propyl substituted)N-ethyl linker with a piperazine biphenyl moiety (D-264) or a piperazine isoquinolin moiety (D-301) (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…Both compounds appeared to be full agonists relative to DA. We chose D-264 as one of the compounds for study since it not only displayed preferential D 3 potency but also exhibited efficacious in vivo activity including potent neuroprotection [19,21]. D-301 was selected because the compound exhibited high potency and very high selectivity for D 3 receptors [18].…”

Section: Introductionmentioning

confidence: 99%

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Efficacy of Hybrid Tetrahydrobenzo[d]thiazole Based Aryl Piperazines D-264 and D-301 at D2 and D3 Receptors

et al. 2015

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In elucidating the role of pharmacodynamic efficacy at D3 receptors in therapeutic effectiveness of dopamine receptor agonists, the influence of study system must be understood. Here two compounds with D3 over D2 selectivity developed in our earlier work, D-264 and D-301, are compared in dopamine receptor-mediated G-protein activation in striatal regions of wild-type and D2 receptor knockout mice and in CHO cells expressing D2 or D3 receptors. In caudate-putamen of D2 knockout mice, D-301 was ~ 3-fold more efficacious than D-264 in activating G-proteins as assessed by [35S]GTP S binding; in nucleus accumbens, D-301 stimulated G-protein activation whereas D-264 did not. In contrast, the two ligands exerted similar efficacy in both regions of wild-type mice, suggesting both ligands activate D2 receptors with similar efficacy. In D2 and D3 receptor-expressing CHO cells, D-264 and D-301 appeared to act in the [35S]GTP S assay as full agonists because they produced maximal stimulation equal to dopamine. Competition for [3H]spiperone binding was then performed to determine Ki/EC50 ratios as an index of receptor reserve for each ligand. Action of D-301, but not D-264, showed receptor reserve in D3 but not in D2 receptor-expressing cells, whereas dopamine showed receptor reserve in both cell lines. G o1 is highly expressed in brain and is important in D2 -like receptor-G protein coupling. Transfection of G o1 in D3- but not D2-expressing CHO cells led to receptor reserve for D-264 without altering receptor expression levels. D-301 and dopamine exhibited receptor reserve in D3-expressing cells both with and without transfection of G o1. Altogether, these results indicate that D-301 has greater intrinsic efficacy to activate D3 receptors than D-264, whereas the two compounds act on D2 receptors with similar intrinsic efficacy. These findings also suggest caution in interpreting Emax values from functional assays in receptor-transfected cell models without accounting for receptor reserve.

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“…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%

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.

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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.

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Bioisosteric Heterocyclic Versions of 7-{[2-(4-Phenyl-piperazin-1-yl)ethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-ol: Identification of Highly Potent and Selective Agonists for Dopamine D3 Receptor with Potent in Vivo Activity

Cited by 47 publications

References 49 publications

The high‐affinity D2/D3 agonist D512 protects PC12 cells from 6‐OHDA‐induced apoptotic cell death and rescues dopaminergic neurons in the MPTP mouse model of Parkinson's disease

The high‐affinity D2/D3 agonist D512 protects PC12 cells from 6‐OHDA‐induced apoptotic cell death and rescues dopaminergic neurons in the MPTP mouse model of Parkinson's disease

Efficacy of Hybrid Tetrahydrobenzo[d]thiazole Based Aryl Piperazines D-264 and D-301 at D2 and D3 Receptors

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

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