Abstract

G-protein-coupled receptors (GPCR) are the largest family of proteins encoded in
the genome, which transduce signals for the most diverse ligands of any receptor
family. GPR68, a transmembrane receptor that can induce physiological effects when
activated by protons, belongs to this class and its considered a promising target for the
treatment of ischemia, as its Gq subunit is involved in the release of calcium, which may
promote stem cell differentiation and make GPR-68 an attractive target for anti-ischemic
candidates. Ogerin, a small molecule containing a triazine core, it’s the only well known
GPR68 ligand, and revealed neuroprotective effects as stimulate Gq subunit, being
considered a lead compound for the design of potential candidates. Thus, through the
use of several drug design strategies and applying Structure-Based Drug Design
(SBDD) approach, four structural classes of triazine derivatives were synthesized,
biologically tested and computationally docked, aiming to continue Structure-Activity
Relationship (SAR) studies. Although the employed synthetic methodologies proved to
be efficient, allowing the obtention of 37 compounds, only three of them could slightly
stimulate GPR68-Gq. Thus, based on the real biological data, combined with the
molecular docking results, it’s first possible to propose that the triazine motif acts as the
pharmacophore, due to its strong HBA tertiary nitrogen group, which can effectively
interact with GPR68. On the other hand, the replacement of a HBD (hydrogen from
amine) group by a HBA (methoxy) at the position 4 of the triazine ring eliminates the
activity, while the replacement of a HBD (hydrogen from hydroxymethyl) by a strong
HBA (cyano) at the ortho position of the phenyl ring increased it. The addition of
fluorines and heterocycles, as well as the removal of the single bond in the benzylamine
ring, didn’t contribute to the potency as well. These findings will help in guiding the
development of the next generation of Ogerin’s derivatives, asses their GPR68-Gq
stimulation, and advance SAR studies, to obtain promising active molecules.