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 GABAA 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.

Figure 1

The neuropeptide galanin binds to three G-protein coupled receptors (GPCRs) with K_d of 1 nmol/L in the brain and spinal cord. PAM, positive allosteric modulator; aa, amino acid. Four million compounds were screened by Roche, Merck, Pfizer, and Johnson & Johnson, but neither agonist nor antagonist was found at 10 μmol/L cut-off. We had to start to look for allosteric ligands but galanin had a half-life of only 2.5 min in the cellular assay, so at 20% occupancy the results were extremely variable and PAMs were missed. We needed a peptidolitically stable galanin receptor agonist (not necessarily subtype selective).

Figure 2

Galanin receptor agonists and positive allosteric modulator. Galanin is the endogenous peptide ligand, not receptor subtype selective. Galnon is a nonpeptidic, systemically active low affinity orthosteric agonist that is not receptor subtype selective. Galmic is a nonpeptidic, systemically active low affinity orthosteric agonist that is not receptor subtype selective. CYM2503 is a systemically active, positive allosteric modulator to the GALR2 receptor.

Figure 3

CYM2503 lowers mortality in seizure models. (A) Lowered mortality in the Li-pilocarpine model of status epilepticus. (B) Lowered mortality in an electroshock-induced seizure model.