Current Topics in Medicinal Chemistry - Volume 19, Issue 26, 2019

G protein-coupled receptors (GPCRs) represent the largest family of proteins targeted by drug design and discovery efforts. Of these efforts, the development of GPCR agonists is highly desirable, due to their therapeutic robust utility in treating diseases caused by deficient receptor signaling. One of the challenges in designing potent and selective GPCR agonists lies in the inability to achieve combined high binding affinity and subtype selectivity, due to the high homology between orthosteric sites among GPCR subtypes. To combat this difficulty, researchers have begun to explore the utility of targeting topographically distinct and less conserved binding sites, namely “allosteric” sites. Pursuing these sites offers the benefit of achieving high subtype selectivity, however, it also can result in a decreased binding affinity and potency as compared to orthosteric agonists. Therefore, bitopic ligands comprised of an orthosteric agonist and an allosteric modulator connected by a spacer and allowing binding with both the orthosteric and allosteric sites within one receptor, have been developed. It may combine the high subtype selectivity of an allosteric modulator with the high binding affinity of an orthosteric agonist and provides desired advantages over orthosteric agonists or allosteric modulators alone. Herein, we review the recent advances in the development of bitopic agonists/activators for various GPCR targets and their novel therapeutic potentials.

Despite extensive efforts to design serotonin 5-HT1A receptor compounds, there are currently no clinically available selective agonists to explore the therapeutic potential of activating this receptor. Commonly used drugs targeting 5-HT1A receptors, such as buspirone or other azapirone compounds, possess only limited selectivity over cross-reacting sites, act as partial agonists for 5-HT1A receptor activation, and are metabolically labile, generating active metabolites. In addition, drug discovery has been hampered by the multiplicity of 5-HT1A receptor subpopulations, expressed in different brain regions, that are coupled to distinct molecular signaling mechanisms and mediate a wide variety of physiological responses, both desired and undesired. In this context, advances in 5-HT1A receptor drug discovery have attracted attention of novel ‘biased agonists’ that are selective, efficacious and preferentially target the brain regions that mediate therapeutic activity without triggering side effects. The prototypical first-in-class compound NLX-101 (a.k.a. F15599; 3-chloro-4-fluorophenyl-[4-fluoro-4-[[(5-methylpyrimidin-2-ylmethyl)amino]methyl]piperidin- 1-yl]methanone), preferentially activates 5-HT1A receptors in cortical regions and exhibits potent, rapidacting and sustained antidepressant-like and procognitive properties in animal models. Here the background has been reviewed that led to the discovery of the class of 1-(1-benzoylpiperidin-4- yl)methanamine derivatives, including NLX-101, as well as recent advances in discovery of novel 5-HT1A receptor biased agonists, notably aryloxyethyl derivatives of 1128;‘(1-benzoylpiperidin-4yl)methanamine which show promising pharmacological activity both in vitro and in vivo. Overall, the results suggest that opportunities exist for innovative drug discovery of selective 5-HT1A receptor biased agonists that may open new avenues for the treatment of CNS disorders involving dysfunction of serotonergic neurotransmission.

The amino terminal domain (ATD) of the metabotropic glutamate (mGlu) receptors contains the orthosteric glutamate recognition site, which is highly conserved across the eight mGlu receptor subtypes. In total, 29 X-ray crystal structures of the mGlu ATD proteins have been reported to date. These structures span across 3 subgroups and 6 subtypes, and include apo, agonist- and antagonist-bound structures. We will discuss the insights gained from the analysis of these structures with the focus on the interactions contributing to the observed group and subtype selectivity for select agonists. Furthermore, we will define the full expanded orthosteric ligand binding pocket (LBP) of the mGlu receptors, and discuss the macroscopic features of the mGlu ATD proteins.