Novel multifunctional dopamine D2/D3 receptors agonists with potential neuroprotection and anti-alpha synuclein protein aggregation properties

被引：21
作者：
Luo, Dan [1 ]
Sharma, Horrick [1 ]
Yedlapudi, Deepthi [1 ]
Antonio, Tamara [2 ]
Reith, Maarten E. A. [2 ]
Dutta, Aloke K. [1 ]
机构：
[1] Wayne State Univ, Dept Pharmaceut Sci, Eugene Applebaum Coll Pharm & Hlth Sci, Detroit, MI 48202 USA
[2] NYU, Dept Psychiat, New York, NY 10016 USA
来源：
BIOORGANIC & MEDICINAL CHEMISTRY | 2016年 / 24卷 / 21期
关键词：
Parkinson's disease; Dopamine agonist; Multifunctional drug; Neuroprotection; Alpha synuclein; Structure activity relationship study; PARKINSONS-DISEASE; ANIMAL-MODELS; HIGH-AFFINITY; PC12; CELLS; IN-VITRO; PATHOGENESIS; CLONING; 6-HYDROXYDOPAMINE; RESERPINE; TOXICITY;
D O I：
10.1016/j.bmc.2016.08.021
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Our ongoing drug development endeavor to design compounds for symptomatic and neuroprotective treatment of Parkinson's disease (PD) led us to carry out a structure activity relationship study based on dopamine agonists pramipexole and 5-OHDPAT. Our goal was to incorporate structural elements in these agonists in a way to preserve their agonist activity while producing inhibitory activity against aggregation of alpha-synuclein protein. In our design we appended various catechol and related phenol derivatives to the parent agonists via different linker lengths. Structural optimization led to development of several potent agonists among which (-)-8a, (-)-14 and (-)-20 exhibited potent neuroprotective properties in a cellular PD model involving neurotoxin 6-OHDA. The lead compounds (-)-8a and (-)-14 were able to modulate aggregation of alpha-synuclein protein efficiently. Finally, in an in vivo PD animal model, compound (-)-8a exhibited efficacious anti-parkinsonian effect. (C) 2016 Elsevier Ltd. All rights reserved.
引用
收藏
页码：5088 / 5102
页数：15
相关论文
共 50 条
[41]   The Dopamine Stabilizer (-)-OSU6162 Occupies a Subpopulation of Striatal Dopamine D2/D3 Receptors: An [11C] Raclopride PET Study in Healthy Human Subjects [J].
Tolboom, Nelleke ;
Berendse, Henk W. ;
Leysen, Josee E. ;
Yaqub, Maqsood ;
van Berckel, Bart N. M. ;
Schuit, Robert C. ;
Ponsen, Mirthe M. ;
Bakker, Esther ;
Hoetjes, Nikie J. ;
Windhorst, Albert D. ;
Carlsson, Maria L. ;
Lammertsma, Adriaan A. ;
Carlsson, Arvid .
NEUROPSYCHOPHARMACOLOGY, 2015, 40 (02) :472-479
[42]   Selective Blockade of Dopamine D3 Receptors Enhances while D2 Receptor Antagonism Impairs Social Novelty Discrimination and Novel Object Recognition in Rats: A Key Role for the Prefrontal Cortex [J].
Watson, David J. G. ;
Loiseau, Florence ;
Ingallinesi, Manuela ;
Millan, Mark J. ;
Marsden, Charles A. ;
Fone, Kevin C. F. .
NEUROPSYCHOPHARMACOLOGY, 2012, 37 (03) :770-786
[43]   Dopamine-nociceptin/orphanin FQ interactions in the substantia nigra reticulata of hemiparkinsonian rats: Involvement of D2/D3 receptors and impact on nigro-thalamic neurons and motor activity [J].
Volta, Mattia ;
Viaro, Riccardo ;
Trapella, Claudio ;
Marti, Matteo ;
Morari, Michele .
EXPERIMENTAL NEUROLOGY, 2011, 228 (01) :126-137
[44]   Concentration of receptor and ligand revisited in a modified receptor binding protocol for high-affinity radioligands: [3H]Spiperone binding to D2 and D3 dopamine receptors [J].
Zhen, Juan ;
Antonio, Tamara ;
Dutta, Aloke K. ;
Reith, Maarten E. A. .
JOURNAL OF NEUROSCIENCE METHODS, 2010, 188 (01) :32-38
[45]   Binding of the Dual-Action Anti-Parkinsonian Drug AG-0029 to Dopamine D2 and Histamine H3 Receptors: A PET Study in Healthy Rats [J].
Ghazanfari, Nafiseh ;
van Waarde, Aren ;
Doorduin, Janine ;
Sijbesma, Jurgen W. A. ;
Kominia, Maria ;
Koelewijn, Martin ;
Attia, Khaled ;
Vallez-Garcia, David ;
Willemsen, Antoon T. M. ;
Heeres, Andre ;
Dierckx, Rudi A. J. O. ;
Visser, Ton J. ;
de Vries, Erik F. J. ;
Elsinga, Philip H. .
MOLECULAR PHARMACEUTICS, 2022, :2287-2298
[46]   Design and synthesis of novel N-sulfonyl-2-indoles that behave as 5-HT6 receptor ligands with significant selectivity for D3 over D2 receptors [J].
Saavedra, Oscar M. ;
Karila, Delphine ;
Brossard, Dominique ;
Rojas, Anne ;
Dupuis, Delphine ;
Gohier, Arnaud ;
la Cour, Clotilde Mannoury ;
Millan, Mark J. ;
Ortuno, Jean-Claude ;
Hanessian, Stephen .
BIOORGANIC & MEDICINAL CHEMISTRY, 2017, 25 (01) :38-52
[47]   Involvement of dopamine D2/D3 receptors and BDNF in the neuroprotective effects of S32504 and pramipexole against 1-methyl-4-phenylpyridinium in terminally differentiated SH-SY5Y cells [J].
Presgraves, SP ;
Borwege, S ;
Millan, MJ ;
Joyce, JN .
EXPERIMENTAL NEUROLOGY, 2004, 190 (01) :157-170
[48]   In vitro characterization of SLV308 (7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolone, monohydrochloride):: A novel partial dopamine D2 and D3 receptor agonist and serotonin 5-HT1A receptor agonist [J].
Glennon, Jeffrey C. ;
Van Scharrenburg, Guus ;
Ronken, Eric ;
Hesselink, Mayke B. ;
Reinders, Jan-Hendrik ;
Van der Neut, Martina ;
Long, Stephen K. ;
Feenstra, Rolf W. ;
McCreary, Andrew C. .
SYNAPSE, 2006, 60 (08) :599-608
[49]   A novel synthesis and pharmacological evaluation of a potential dopamine D1/D2 agonist:: 1-Propyl-1,2,3,4,4a,5,10,10-aoctahydrobenzo[g]quinoline-6,7-diol [J].
Liu, Danyang ;
Dijkstra, Durk ;
de Vries, Jan B. ;
Wikstrom, Hakan V. .
BIOORGANIC & MEDICINAL CHEMISTRY, 2008, 16 (06) :3438-3444
[50]   Modification of agonist binding moiety in hybrid derivative 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-1-ol/-2-amino versions: Impact on functional activity and selectivity for dopamine D2/D3 receptors [J].
Gopishetty, Bhaskar ;
Zhang, Suhong ;
Kharkar, Prashant S. ;
Antonio, Tamara ;
Reith, Maarten ;
Dutta, Aloke K. .
BIOORGANIC & MEDICINAL CHEMISTRY, 2013, 21 (11) :3164-3174
12345