Pharmacological andSARanalysis of theLINS01 compounds at the human histamine H₁, H₂, and H₃receptors

Abstract

Histamine is a transmitter that activates the four receptors H R to H R. The H R 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 H R over the H R. Here, we describe their pharmacological properties at the human H R and H R in parallel with the H R, thus providing a full analysis of these compounds as histamine receptor ligands through reporter gene assays. Eight of the nine LINS01 compounds inhibited H R-induced histamine responses, but no inhibition of H R-induced responses was seen. Three compounds were weakly able to inhibit H R-induced responses. No agonist responses were seen to any of the compounds at any receptor. SAR analysis shows that the N-methyl group improves H R affinity while the N-phenyl group is detrimental. The methoxy derivative, LINS01009, had the highest affinity.

The Novel H4R Antagonist 1-[(5-Chloro-2,3-Dihydro-1-Benzofuran-2-Yl)Methyl]-4-Methyl-Piperazine (LINS01007) Attenuates Several Symptoms in Murine Allergic Asthma

“…The compounds LINS01005 and LINS01007 were prepared and characterized as previously described by Corrêa et al [15][16][17]. The purity of the compounds was >95%, checked by elemental analysis (C, H and N) and chromatography (HPLC) assessments.…”

“…Both compounds showed antagonistic effect on activation assays using BRET constructions with Gα i -1 protein, and no activation of the β-arrestin signaling pathway was observed. Additionally, these compounds also showed negligible affinity for H 1 R or H 2 R [17].…”

“…In the last years our group have been exploring the potential of 1-(2,3-dihydrobenzofuran-2-yl)methylpiperazines (LINS01 series) as ligands of histamine receptors, especially on H 3 R and H 4 R [15][16][17]. The affinity of these compounds is dependent of specific characteristics of the molecule, but in general preference for H 3 R was observed for these compounds.…”

Evaluation of the histamine H3 receptor antagonists from LINS01 series as cholinesterases inhibitors: Enzymatic and modeling studies

“…In the last years our group was devoted to designing and evaluating H 3 R ligands, with special mention to compounds containing the 1-[(2,3-dihydrobenzofuran-1-yl) methyl]piperazine scaffold (LINS01 series, Figure 1; Corrêa et al, 2019Corrêa et al, , 2021Corrêa, Barbosa, et al, 2017;Corrêa, Varela, et al, 2017). Some compounds from the set showed nanomolar affinity and antagonistic effect on H 3 R (Corrêa et al, 2021;Corrêa, Barbosa, et al, 2017).…”

“…The compounds from LINS01 series were prepared as previously described by our group (Corrêa et al, 2019(Corrêa et al, , 2020(Corrêa et al, , 2021Corrêa, Barbosa, et al, 2017; see Supplementary Material) and converted into the maleate salts to obtain >95% purity. The compounds were then evaluated for their inhibitory activity on Electrophorus electricus AChE (eeAChE) and equine serum BChE (eqBChE) in a 96well microplate following the Ellman's method (Ellman et al, 1961), adapted from the described by Mathew and Subramanian (Mathew & Subramanian, 2014).…”