Recent Advances in the Drug Discovery and Development of Dualsteric/ Bitopic Activators of G Protein-Coupled Receptors

Abstract

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.

Evaluation of Substituted N-Phenylpiperazine Analogs as D3 vs. D2 Dopamine Receptor Subtype Selective Ligands

“…While the identification of a ligand that can interact with a dualistic ligand binding mode may not be applicable for the development of receptor subtype selective ligands for every GPCR subfamily, it appears not to be unique to the dopamine receptor subtypes. Bitopic ligands have also been reported for other GPCRs, including the muscarinic and angiotensin II receptors [ 46 , 47 , 48 ]. Furthermore, binding data provided by NIMH Psychoactive Drug Screening Program (PSDP) indicated that compound 6a had reduced affinity at the 5-HT1A receptor, which is a common off-site binding component that has limited the development of in-vivo D3 dopamine receptor selective imaging agents.…”

Opioid Ligands Addressing Unconventional Binding Sites and More Than One Opioid Receptor Subtype

“…The inclusion of both an orthosteric ligand and allosteric modulator have been demonstrated to achieve higher affinity and potency (via orthosteric ligand) and selectivity (via allosteric modulator), enhance off-rates and decrease intrinsic efficacy. [128] Although bitopic ligands are comprised of a combination of an orthosteric and an allosteric part, nonetheless they convey unique pharmacological properties. [77,79,108,120,121,[128][129][130][131][132][133][134] Bitopic ligands are formed by connecting the aforementioned two distinct parts with a suitable linker moiety resulting in a single chemical entity, that interacts simultaneously with the orthosteric binding site and allosteric binding site (Scheme 7).…”

“…[128] Although bitopic ligands are comprised of a combination of an orthosteric and an allosteric part, nonetheless they convey unique pharmacological properties. [77,79,108,120,121,[128][129][130][131][132][133][134] Bitopic ligands are formed by connecting the aforementioned two distinct parts with a suitable linker moiety resulting in a single chemical entity, that interacts simultaneously with the orthosteric binding site and allosteric binding site (Scheme 7). [108] Thus, bitopic ligands are bifunctional ligands similarly to the bivalent ligands previously presented herein; while the latter are designed to bind in two binding sites belonging to two different receptors, the former are designed to bind in two binding sites within the same receptor.…”

“…Bitopic or dualsteric ligands are the ligands which bind to both the orthosteric and allosteric binding sites of a single receptor protomer. The inclusion of both an orthosteric ligand and allosteric modulator have been demonstrated to achieve higher affinity and potency (via orthosteric ligand) and selectivity (via allosteric modulator), enhance off‐rates and decrease intrinsic efficacy [128] . Although bitopic ligands are comprised of a combination of an orthosteric and an allosteric part, nonetheless they convey unique pharmacological properties [77,79,108,120,121,128–134] .…”

C-2-Linked Dimeric Strychnine Analogues as Bivalent Ligands Targeting Glycine Receptors

“…Bivalent ligands are defined as compounds containing two pharmacophoric entities linked by an appropriate spacer that ideally enables simultaneous binding to two distinct primary binding sites of the target macromolecules. , They should be distinguished from bitopic ligands that consist of a primary pharmacophore targeting the orthosteric binding site connected by a linker to a secondary pharmacophore occupying the allosteric binding pocket. − The bivalent ligand approach has been widely used for G-protein-coupled receptors (GPCRs), such as opioid, , adrenergic, dopamine, , serotonin, muscarinic, cannabinoid, and melatonin , receptors. Here, numerous bivalent ligands have been designed to bridge the orthosteric binding sites of two assembled receptors and used as pharmacological tools to study the structure and functional properties of dimeric GPCRs. , Based on GPCR crystal structures, major advances have recently been achieved in heterobivalent ligands targeting dimers of two different GPCRs .…”