Literature DB >> 24960209

Multifunctional D2/D3 agonist D-520 with high in vivo efficacy: modulator of toxicity of alpha-synuclein aggregates.

Gyan Modi1, Chandrashekhar Voshavar, Sanjib Gogoi, Mrudang Shah, Tamara Antonio, Maarten E A Reith, Aloke K Dutta.   

Abstract

We have developed a series of dihydroxy compounds and related analogues based on our hybrid D2/D3 agonist molecular template to develop multifunctional drugs for symptomatic and neuroprotective treatment for Parkinson's disease (PD). The lead compound (-)-24b (D-520) exhibited high agonist potency at D2/D3 receptors and produced efficacious activity in the animal models for PD. The data from thioflavin T (ThT) assay and from transmission electron microscopy (TEM) analysis demonstrate that D-520 is able to modulate aggregation of alpha-synuclein (αSN). Additionally, coincubation of D-520 with αSN is able to reduce toxicity of preformed aggregates of αSN compared to control αSN alone. Finally, in a neuroprotection study with dopaminergic MN9D cells, D-520 clearly demonstrated the effect of neuroprotection from toxicity of 6-hydroxydopamine. Thus, compound D-520 possesses properties characteristic of multifunctionality conducive to symptomatic and neuroprotective treatment of PD.

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Year:  2014        PMID： 24960209      PMCID： PMC4140597          DOI： 10.1021/cn500084x

Source DB:  PubMed          Journal:  ACS Chem Neurosci        ISSN： 1948-7193            Impact factor:   4.418


  51 in total

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Authors:  Juan Zhen; Tamara Antonio; Aloke K Dutta; Maarten E A Reith
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Review 8.  Alpha-synuclein and Parkinson's disease.

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Review 9.  Understanding the molecular causes of Parkinson's disease.

Authors:  A Wood-Kaczmar; S Gandhi; N W Wood
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Authors:  Gyan Modi; Tamara Antonio; Maarten Reith; Aloke Dutta
Journal:  J Med Chem       Date:  2014-02-12       Impact factor: 7.446
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  9 in total

Review 1.  Dopamine D3 receptor: A neglected participant in Parkinson Disease pathogenesis and treatment?

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Review 2.  α-Synuclein aggregation modulation: an emerging approach for the treatment of Parkinson's disease.

Authors:  Sushil K Singh; Aloke Dutta; Gyan Modi
Journal:  Future Med Chem       Date:  2017-06-20       Impact factor: 3.808

Review 3.  Advances and challenges in the search for D2 and D3 dopamine receptor-selective compounds.

Authors:  Amy E Moritz; R Benjamin Free; David R Sibley
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4.  Neurotoxin mechanisms and processes relevant to Parkinson's disease: an update.

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5.  A novel iron (II) preferring dopamine agonist chelator D-607 significantly suppresses α-syn- and MPTP-induced toxicities in vivo.

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Journal:  Neuropharmacology       Date:  2017-05-19       Impact factor: 5.250

Review 6.  Rasagiline and selegiline modulate mitochondrial homeostasis, intervene apoptosis system and mitigate α-synuclein cytotoxicity in disease-modifying therapy for Parkinson's disease.

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7.  Development of a Highly Potent D2/D3 Agonist and a Partial Agonist from Structure-Activity Relationship Study of N(6)-(2-(4-(1H-Indol-5-yl)piperazin-1-yl)ethyl)-N(6)-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine Analogues: Implication in the Treatment of Parkinson's Disease.

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Journal:  J Med Chem       Date:  2015-11-30       Impact factor: 7.446

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

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9.  Targeting alpha synuclein and amyloid beta by a multifunctional, brain-penetrant dopamine D2/D3 agonist D-520: Potential therapeutic application in Parkinson's disease with dementia.

Authors:  Deepthi Yedlapudi; Liping Xu; Dan Luo; Gregory B Marsh; Sokol V Todi; Aloke K Dutta
Journal:  Sci Rep       Date:  2019-12-23       Impact factor: 4.379
  9 in total

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