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

Autor(es)

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]

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF CHEMICAL SCIENCES; v. 132, n. 1 DEC 2019.
• Citações Web of Science: 0

Resumo

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)

• Processo FAPESP: 17/05441-6 - Diidrobenzofuranil-fenilpiperazinas como agentes vasodilatadores: síntese e avaliação de análogos do LINS01005
• Beneficiário: Gustavo Ariel Borges Fernandes
• Linha de fomento: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 18/03918-2 - Avaliação da atividade antiparasitária e da citotoxicidade de derivados de produtos naturais em Trypanosoma cruzi: planejamento e síntese de análogos potencialmente superiores
• Beneficiário: Marina Themoteo Varela
• Linha de fomento: Bolsas no Brasil - Doutorado
• Processo FAPESP: 18/04488-1 - Ligantes histaminérgicos e dopaminérgicos como agentes pró-cognitivos: síntese e avaliação de ariloxialquilpiperazinas
• Beneficiário: Cecília Maria Simões de Queiroz Aranha
• Linha de fomento: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 16/25028-3 - Anti-histamínicos H3R/H4R como agentes pró-cognitivos: uma abordagem multialvo
• Beneficiário: João Paulo dos Santos Fernandes
• Linha de fomento: Auxílio à Pesquisa - Regular