Profiling of LINS01 compounds at human dopamine D-2 and D-3 receptors

Author(s)

Correa, Michelle F. ^[1] ; Reiner, David ^[2] ; Fernandes, Gustavo A. B. ^[1] ; Varela, Marina T. ^[1] ; Aranha, Cecilia M. S. Q. ^[1] ; Stark, Holger ^[2] ; Fernandes, Joao Paulo S. ^[1]

Affiliation

^[1] Univ Fed Sao Paulo, Dept Pharmaceut Sci, Rua Sao Nicolau 210, BR-09913030 Diadema, SP - Brazil

^[2] Heinrich Heine Univ Dusseldorf, Inst Pharmaceut & Med Chem, Univ Str 1, D-40225 Dusseldorf - Germany

• Document type: Journal article
• Source: JOURNAL OF CHEMICAL SCIENCES; v. 132, n. 1 DEC 2019.
• Web of Science Citations: 0

Abstract

Histamine and dopamine neuronal pathways display interesting overlapping in the CNS, especially in the limbic areas, making them very attractive to designing drugs with synergistic and/or additive effects. The roles of these systems to treat schizophrenia, drug addiction, Parkinson's and Alzheimer's diseases, among others are widely known. The LINS01 compounds were previously reported as histamine H-3 receptor (H3R) antagonists and some of them are under evaluation in rodent memory models. Considering their pharmacological potential and similarities to literature dopamine D-2 receptor (D2R) and dopamine D-3 receptor (D3R) ligands, this work aimed to evaluate these compounds as ligands these receptors by using {[}H-3]spiperone displacement assays. A set of 11 compounds containing the dihydrobenzofuranyl-piperazine core with substituents at 5-position of dihydrobenzofuran ring and at the piperazine nitrogen was examined. The compounds showed low to moderate affinities at both, D2R and D3R. N-Phenyl compounds LINS01005 (1d), LINS01011 (1h), LINS01012 (1i) and LINS01016 (1k) showed the highest affinities in the set to D3R (K-i 0.3-1.5 mu M), indicating that N-phenylpiperazine moiety increases the affinity to this receptor subtype with some selectivity, since they showed lower affinities to D2R (K-i 1.3-5.5 mu M). With the LINS01 compounds showing moderate binding affinity, new lead structures for optimization with regards to combined H3R and D2R/D3R-ligands are provided. (AU)

• FAPESP's process: 17/05441-6 - Dihydrobenzofuranyl-phenylpiperazines as vasodilating agents: synthesis and evaluation of LINS01005 analogs
• Grantee: Gustavo Ariel Borges Fernandes
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 18/03918-2 - Evaluation of the antiparasitic activity and cytotoxicity of natural products derivatives in Trypanosoma cruzi: design and synthesis of analogues potentially superior
• Grantee: Marina Themoteo Varela
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 18/04488-1 - Histaminergic and dopaminergic ligands as procognitive agents: synthesis and evaluation of aryloxyalkylpiperazines
• Grantee: Cecília Maria Simões de Queiroz Aranha
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 16/25028-3 - Antihistamines H3R/H4R as procognitive agents: a multitarget approach
• Grantee: João Paulo dos Santos Fernandes
• Support Opportunities: Regular Research Grants