Positive allosteric modulators to peptide GPCRs: a promising class of drugs

Abstract

The task of finding selective and stable peptide receptor agonists with low molecular weight, desirable pharmacokinetic properties and penetrable to the blood-brain barrier has proven too difficult for many highly coveted drug targets, including receptors for endothelin, vasoactive intestinal peptide and galanin. These receptors and ligand-gated ion channels activated by structurally simple agonists such as glutamate, glycine and GABA present such a narrow chemical space that the design of subtype-selective molecules capable of distinguishing a dozen of glutamate and GABA receptor subtypes and possessing desirable pharmacokinetic properties has also been problematic. In contrast, the pharmaceutical industry demonstrates a remarkable success in developing 1,4-benzodiazepines, positive allosteric modulators (PMAs) of the GABA A receptor. They were synthesized over 50 years ago and discovered to have anxiolytic potential through an in vivo assay. As exemplified by Librium, Valium and Dormicum, these allosteric ligands of the receptor became the world's first blockbuster drugs. Through molecular manipulation over the past 2 decades, including mutations and knockouts of the endogenous ligands or their receptors, and by in-depth physiological and pharmacological studies, more peptide and glutamate receptors have become well-validated drug targets for which an agonist is sought. In such cases, the pursuit for PAMs has also intensified, and a working paradigm to identify drug candidates that are designed as PAMs has emerged. This review, which focuses on the general principles of finding PAMs of peptide receptors in the 21st century, describes the workflow and some of its resulting compounds such as PAMs of galanin receptor 2 that act as potent anticonvulsant agents.

Preclinical evaluation of intravenous NAX 810‐2, a novel GalR2‐preferring analog, for anticonvulsant efficacy and pharmacokinetics

“…Previous efforts to develop compounds that act on galanin receptors have included the small molecules galmic and galnon, galanin peptide fragments, and galanin allosteric modulators . Galmic and galnon were hindered as novel therapeutics due to low affinity (i.e., compared to peptide ligands) and a lack of selectivity for GalR1 and/or GalR2 .…”

“…Previous efforts to develop compounds that act on galanin receptors have included the small molecules galmic 6,29,30 and galnon, 6,31 galanin peptide fragments, 6 and galanin allosteric modulators. 32 Galmic and galnon were hindered as novel therapeutics due to low affinity (i.e., compared to peptide ligands) and a lack of selectivity for GalR1 and/or GalR2. 6,33 Galanin and galanin peptide fragments have proven effective against seizures when administered centrally, 6,25 although systemic administration has been challenged by metabolic stability and lack of blood-brain barrier penetration.…”

The galanin receptor agonist, galnon, attenuates cocaine‐induced reinstatement and dopamine overflow in the frontal cortex

“…Galnon (Bachem, Torrance, CA, USA) was sonicated in 1% dimethyl sulfoxide. Galnon is a non‐selective galanin receptor agonist (K d = 1 μM) with a half‐life of approximately 60 minutes (Bartfai & Wang ). Galnon was injected 20–30 minutes before cocaine based on effective pre‐treatment schedules in rodents (Lu et al .…”

Co-released Norepinephrine and Galanin Act on Different Timescales to Promote Stress-Induced Anxiety-Like Behavior

“…The nonspecific galanin receptor agonist galnon (Bachem, Torrance, CA, USA), which has a half-life of approximately 60 min (30), was dissolved in 0.9% sterile saline with 1% DMSO. Mice were injected with vehicle or galnon (2 mg/kg, i.p.)…”