Bivalent dopamine agonists with co-operative binding and functional activities at dopamine D2 receptors, modulate aggregation and toxicity of alpha synuclein protein.

Autor: Dinda B; Wayne State University, Department of Pharmaceutical Sciences, Detroit, MI 48202, United States., Das B; Wayne State University, Department of Pharmaceutical Sciences, Detroit, MI 48202, United States., Biswas S; Wayne State University, Department of Pharmaceutical Sciences, Detroit, MI 48202, United States., Sharma H; Wayne State University, Department of Pharmaceutical Sciences, Detroit, MI 48202, United States., Armstrong C; Wayne State University, Department of Pharmaceutical Sciences, Detroit, MI 48202, United States., Yedlapudi D; Wayne State University, Department of Pharmaceutical Sciences, Detroit, MI 48202, United States., Antonio T; New York University, Department of Psychiatry, New York, NY 10016, United States., Reith M; New York University, Department of Psychiatry, New York, NY 10016, United States., Dutta AK; New York University, Department of Psychiatry, New York, NY 10016, United States. Electronic address: adutta@wayne.edu.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2023 Jan 15; Vol. 78, pp. 117131. Date of Electronic Publication: 2022 Dec 16.
DOI: 10.1016/j.bmc.2022.117131
Abstrakt: To follow up on our previous report on bivalent compounds exhibiting potent co-operative binding at dopamine D2 receptors, we modified the structure of the linker in our earlier bivalent molecules (S)-6-((9-(((R)-5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)nonyl)-(propyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol (Ia) and (S)-6-((10-(((R)-5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)decyl)(propyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol (Ib) (Fig. 1) connecting the two pharmaophoric moieties to observe any tolerance in maintaining similar affinities and potencies. Specifically, we introduced aromatic and piperazine moieties in the linker to explore their effect. Overall, similar activities at D2 receptors as observed in our earlier study was maintained in the new molecules e.g. (6S,6'S)-6,6'-((1,4-phenylenebis(ethane-2,1-diyl))bis(propylazanediyl))bis(5,6,7,8-tetrahydronaphthalen-1-ol) (D-382) (Ki, D2 = 3.88 nM). The aromatic moiety in D-382 was next functionalized by introducing hydroxyl groups to mimic polyhydroxy natural products which are known to interact with amyloidogenic proteins. Such a transformation resulted in development of compounds like 2,5-bis(2-(((S)-5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)benzene-1,4-diol (D-666) (Ki, D2 = 7.62 nM) which retained similar affinity and potency at D2 receptors. Such dihydroxyl compounds turned out to be potent inhibitors against aggregation and toxicity of recombinant alpha synuclein protein. The work reported here is in line with our overall goal to develop multifunctional dopamine agonist for symptomatic and disease modifying treatment of Parkinson's disease.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2022 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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