Pharmacological and SAR analysis of the LINS01 compounds at the human histamine H-1, H-2, and H-3 receptors

Autor(es)

Correa, Michelle Fidelis ^[1] ; Ramos Barbosa, Alefe Jhonatas ^[1] ; Borges Fernandes, Gustavo Ariel ^[1] ; Baker, Jillian G. ^[2] ; dos Santos Fernandes, Joao Paulo ^[1]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Dept Ciencias Farmaceut, Diadema - Brazil

^[2] Univ Nottingham, Sch Life Sci, Cell Signalling Res Grp, Nottingham - England

• Tipo de documento: Artigo Científico
• Fonte: CHEMICAL BIOLOGY & DRUG DESIGN; v. 93, n. 1, p. 89-95, JAN 2019.
• Citações Web of Science: 2

Resumo

Histamine is a transmitter that activates the four receptors H1R to H4R. The H3R is found in the nervous system as an autoreceptor and heteroreceptor, and controls the release of neurotransmitters, making it a potential drug target for neuropsychiatric conditions. We have previously reported that the 1-(2,3-dihydro-1-benzofuran-2-yl)methylpiperazines (LINS01 compounds) have the selectivity for the H3R over the H4R. Here, we describe their pharmacological properties at the human H1R and H2R in parallel with the H3R, thus providing a full analysis of these compounds as histamine receptor ligands through reporter gene assays. Eight of the nine LINS01 compounds inhibited H3R-induced histamine responses, but no inhibition of H2R-induced responses was seen. Three compounds were weakly able to inhibit H1R-induced responses. No agonist responses were seen to any of the compounds at any receptor. SAR analysis shows that the N-methyl group improves H3R affinity while the N-phenyl group is detrimental. The methoxy derivative, LINS01009, had the highest affinity. (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: 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
• Processo FAPESP: 16/23139-2 - Síntese e avaliação biológica de compostos da série LINS01 como agentes pró-cognitivos: uma abordagem multialvo
• Beneficiário: Michelle Fidelis Corrêa
• Linha de fomento: Bolsas no Brasil - Doutorado