Novel potent (dihydro)benzofuranyl piperazines as human histamine receptor ligands - Functional characterization and modeling studies on H-3 and H(4 )receptors

Author(s):Show less -

Corre, Michelle F. ^[1] ; Balico-Silva, Andre L. ^[2] ; Kiss, Dora J. ^[3] ; Fernandes, Gustavo A. B. ^[1] ; Maraschin, Jhonatan C. ^[2] ; Parreiras-e-Silva, Lucas T. ^[2] ; Varela, Marina T. ^[1] ; Simoes, Sarah C. ^[2] ; Bouvier, Michel ^[4] ; Keseru, Gyorgy M. ^[3] ; Costa-Neto, Claudio M. ^[2] ; Fernandes, Joao Paulo S. ^[1]

Affiliation

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

^[2] Univ Sao Paulo, Fac Med Ribeir ao Preto, Dept Bioquim & Imunol, Ribeirao Preto, SP - Brazil

^[3] Res Ctr Nat Sci, Budapest - Hungary

^[4] Univ Montreal, Inst Res Immunol & Canc, Dept Biochem & Mol Med, Montreal, PQ - Canada

• Document type: Journal article
• Source: Bioorganic & Medicinal Chemistry; v. 30, JAN 15 2021.
• Web of Science Citations: 0

Abstract

Histamine acts through four different receptors (H1R-H4R), the H3R and H4R being the most explored in the last years as drug targets. The H3R is a potential target to treat narcolepsy, Parkinson's disease, epilepsy, schizophrenia and several other CNS-related conditions, while H4R blockade leads to anti-inflammatory and immunomodulatory effects. Our group has been exploring the dihydrobenzofuranyl-piperazines (LINS01 series) as human H3R/H4R ligands as potential drug candidates. In the present study, a set of 12 compounds were synthesized from adequate (dihydro)benzofuran synthons through simple reactions with corresponding piperazines, giving moderate to high yields. Four compounds (1b, 1f, 1g and 1h) showed high hH(3)R affinity (pK(i) > 7), compound 1h being the most potent (pK(i) 8.4), and compound if showed the best efficiency (pKi 8.2, LE 0.53, LLE 5.85). BRET-based assays monitoring G alpha(i) activity indicated that the compounds are potent antagonists. Only one compound (2c, pK(i) 7.1) presented high affinity for hH(4)R. In contrast to what was observed for hH(3)R, it showed partial agonist activity. Docking experiments indicated that bulky substituents occupy a hydrophobic pocket in hH(3)R, while the N-allyl group forms favorable interactions with hydrophobic residues in the TM2, 3 and 7, increasing the selectivity towards hH(3)R. Additionally, the importance of the indole NH in the interaction with Glu5.46 from hH(4)R was confirmed by the modeling results, explaining the affinity and agonistic activity of compound 2c. The data reported in this work represent important findings for the rational design of future compounds for hH(3)R and hH(4)R. (AU)

• FAPESP's process: 16/24120-3 - Study of non-canonical roles of G proteins as new signaling mechanisms with impact on discovery and development of new drugs
• Grantee: Lucas Tabajara Parreiras e Silva
• Support Opportunities: Research Grants - Young Investigators Grants
• 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: 12/20148-0 - Development of new ligands/drugs with selective agonism action (biased agonism) for receptors of the renin-angiotensin and kallikrein-kinin systems: new properties and new biotechnological applications
• Grantee: Claudio Miguel da Costa Neto
• Support Opportunities: Research Projects - Thematic Grants
• 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
• 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: 18/00153-5 - Role of bradykinin B2 receptors in the modulation of defensive reactions related to panic: intracellular signalling pathways involved and interaction with µ-opioid receptor
• Grantee: Jhonatan Christian Maraschin
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 16/08920-0 - Comparative analysis of the AT1 receptor signaling profile after activation by balanced and biased agonists by proteomic approach
• Grantee: Sarah Capelupe Simões
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 16/23139-2 - Synthesis and biological evaluation of the LINS01 series as procognitive agents: a multitarget approach
• Grantee: Michelle Fidelis Corrêa
• Support Opportunities: Scholarships in Brazil - Doctorate