Corrêa MF et al. (2017), Pharmacological Characterization of 5-Substitut...

ECB-ART-45899

Front Pharmacol 2017 Nov 14;8:825. doi: 10.3389/fphar.2017.00825.

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Pharmacological Characterization of 5-Substituted 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazines: Novel Antagonists for the Histamine H3 and H4 Receptors with Anti-inflammatory Potential.

Corrêa MF , Barbosa ÁJR , Teixeira LB , Duarte DA , Simões SC , Parreiras-E-Silva LT , Balbino AM , Landgraf RG , Bouvier M , Costa-Neto CM , Fernandes JPS .

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The histamine receptors (HRs) are traditional G protein-coupled receptors of extensive therapeutic interest. Recently, H3R and H4R subtypes have been targeted in drug discovery projects for inflammation, asthma, pain, cancer, Parkinson''s, and Alzheimer''s diseases, which includes searches for dual acting H3R/H4R ligands. In the present work, nine 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine (LINS01 series) molecules were synthesized and evaluated as H3R and H4R ligands. Our data show that the N-allyl-substituted compound LINS01004 bears the highest affinity for H3R (pKi 6.40), while the chlorinated compound LINS01007 has moderate affinity for H4R (pKi 6.06). In addition, BRET assays to assess the functional activity of Gi1 coupling indicate that all compounds have no intrinsic activity and act as antagonists of these receptors. Drug-likeness assessment indicated these molecules are promising leads for further improvements. In vivo evaluation of compounds LINS01005 and LINS01007 in a mouse model of asthma showed a better anti-inflammatory activity of LINS01007 (3 g/kg) than the previously tested compound LINS01005. This is the first report with functional data of these compounds in HRs, and our results also show the potential of their applications as anti-inflammatory.

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Genes referenced: LOC115919910 LOC590297

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	FIGURE 1. Characteristics considered in the design of LINS compounds 1a–i; green – aromatic core; orange – polar group; blue – additional lipophilic group.
	FIGURE 2. Reaction scheme for the synthesis of LINS01 compounds.
	FIGURE 3. Binding and functional characterization of the compounds in the H3R and H4R. Competition dose–response binding curves for selected compounds show that they presented lower affinity for either H3R (A) or H4R (B), as compared with histamine and selective ligands, with Ki values varying from high nanomolar to low micromolar. Functional assays in the H3R (C) reveal that all compounds do not trigger Gi activation, suggesting that they may behave as antagonists in this receptor. In the H4R (D) a similar profile was observed. Antagonistic assays show that all tested compounds when preincubated at 10,000 nM were able to fully block histamine activity in the H3R (E) and H4R (F), except for compound 1f that only partially blocked histamine activity on H4R, probably due to a weak agonistic effect in high concentrations. Data were obtained from at least three independent experiments performed in duplicate. It is also interesting to note that either on H3R or on H4R some compounds displayed a profile that suggests a mild inverse agonist activity, as can be observed by an inverse value of BRET as compared to histamine.
	FIGURE 4. Possible characteristics involved in H3R binding; green – aryl or heteroaryl; orange – polar group; blue – lipophilic group; yellow – bulky group. The yellow group may define the selectivity for the H3R.

References [+] :

Cheng, Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. 1973, Pubmed