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Positive allosteric modulators to peptide GPCRs: a promising class of drugs.
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PMID:  23624758     Owner:  NLM     Status:  MEDLINE    
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.
Tamas Bartfai; Ming-wei Wang
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Publication Detail:
Type:  Journal Article; Review     Date:  2013-04-29
Journal Detail:
Title:  Acta pharmacologica Sinica     Volume:  34     ISSN:  1745-7254     ISO Abbreviation:  Acta Pharmacol. Sin.     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-07-05     Completed Date:  2014-07-06     Revised Date:  2014-10-01    
Medline Journal Info:
Nlm Unique ID:  100956087     Medline TA:  Acta Pharmacol Sin     Country:  United States    
Other Details:
Languages:  eng     Pagination:  880-5     Citation Subset:  IM    
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MeSH Terms
Allosteric Regulation / drug effects,  physiology
Anti-Anxiety Agents / chemistry,  metabolism*,  pharmacology*
Anticonvulsants / chemistry,  metabolism*,  pharmacology
Galanin-Like Peptide / chemistry,  metabolism,  physiology
Receptor, Galanin, Type 2 / chemistry,  metabolism
Receptors, GABA-A / chemistry,  metabolism*
Receptors, Glutamate / chemistry,  metabolism
Receptors, Peptide / chemistry,  metabolism
Reg. No./Substance:
0/Anti-Anxiety Agents; 0/Anticonvulsants; 0/Galanin-Like Peptide; 0/Receptor, Galanin, Type 2; 0/Receptors, GABA-A; 0/Receptors, Glutamate; 0/Receptors, Peptide

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Journal Information
Journal ID (nlm-ta): Acta Pharmacol Sin
Journal ID (iso-abbrev): Acta Pharmacol. Sin
ISSN: 1671-4083
ISSN: 1745-7254
Publisher: Nature Publishing Group
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Copyright © 2013 CPS and SIMM
Received Day: 03 Month: 12 Year: 2012
Accepted Day: 07 Month: 02 Year: 2013
Print publication date: Day: 05 Month: 07 Year: 2013
Electronic publication date: Day: 29 Month: 04 Year: 2013
Volume: 34 Issue: 7
First Page: 880 Last Page: 885
PubMed Id: 23624758
ID: 4002610
Publisher Item Identifier: aps201320
DOI: 10.1038/aps.2013.20

Positive allosteric modulators to peptide GPCRs: a promising class of drugs
Tamas Bartfai1*
Ming-wei Wang2
1Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA
2The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai 201203, China


Allosteric modulators of proteins are well known. They interact with a site other than the binding site of the enzyme substrate (allosteric). In the case of many biosynthetic enzymes, their characterization was pioneered by Changeux and Pardee1,2,3,4,5,6,7, who investigated where do the molecules (eg, feedback inhibitors of amino acid) bind and how does nucleotide biosynthesis on the enzyme catalyze the first step in the cascade4. The key examples of allosteric modulator characterization are the detailed studies on aspartic transcarbamylase and its feedback inhibition4,5. Other examples of allosteric actions involve non-enzymatic proteins such as the oxygen carrier hemoglobin, whose affinity is regulated by protons through the Bohr effect without involving binding to the O2 site, or by 2,3-bisphosphoglycerate binding to an allosteric site on hemoglobin that affects O2 trapping8,9.

Pharmacological uses of receptor allosteric modulators

The pharmacological utilization of allosteric sites was either unconscious or unplanned, because endogenous ligand binding to orthosteric sites or the receptor itself was not defined in molecular terms. When drug molecules were tested in functional assays, the molecular identity of the binding site was not questioned and determined: only functional changes were measured. Thus, it did not matter for the functionality “black box” assay whether the drug molecule is an agonist binding to the orthosteric site of a receptor where endogenous ligand also binds, or it interacts with an allosteric site and acts as a positive allosteric modulator (PAM). When Leo Sternbach10,11 synthesized Valium, a 1,4-benzodiazepine, the molecule was tested in vivo in a rodent anxiety model. Due to the fact that it was highly efficacious and acutely safe, it never mattered if Valium binds to an allosteric site on one subunit of the heteropentameric GABAA receptor or to its coupled chloride channel. Today, allosteric ligands are also introduced for other pentameric ligand-gated ion channels such as α7 nicotinic acetylcholine receptor12 and G-protein coupled receptors (GPCRs). The latter represent the largest class of cell surface proteins and the major receptor class for neuropeptides including GABA receptors13,14,15.

In today's target-based drug discovery, a protein molecule, eg, a peptide receptor, is identified as a drug target based on the physiological and pathophysiological effects caused by mutations in its agonist or in the receptor molecule per se14,15. We are constantly searching for selective, high-affinity ligands to these putative drug targets via high-throughput molecular and cellular screening assays (HTS), which can be designed to identify ligands that bind either to the orthosteric or allosteric site of a receptor16,17.

The pharmacological application of metabotropic glutamate receptors (mGluRs) and glutamate-activated ion channels, such as NMDA and AMPA receptors, is rather limited by the fact that the endogenous ligand glutamate is a chemically simple molecule: its binding site (the orthosteric site) occupies a very narrow chemical space for the design of receptor subtype-selective exogenous agonists, although such compounds, eg, the mGluR2/3 agonist, could serve as an anti-psychotic agent18. It became clear to drug developers at Roche19,20,21, Merck22,23 and later in the entire industry24 that if there were allosteric sites on these receptors, they might hold promise. Drugs that bind to these sites would only be effective when an endogenous agonist occupies the orthosteric site, meaning that the biological rhythm of agonist action is dictated by factors that regulate the release of the endogenous ligand. The allosteric molecules that enhanced agonist action, when identified, have proven to be safe and caused no desensitization, a feature different from directly acting agonists in the monoaminergic system or of NK1 receptors.

Screening for receptor allosteric modulators

The problem in identifying allosteric modulators has been that there are no inferences about the chemical structure of allosteric modulators. Until one or a few allosteric modulators, which bind in the presence of the endogenous ligand or an agonist that occupies the orthosteric site, are attributed to a given receptor, even the existence of an allosteric binding site is in question. Thus, diverse chemical libraries are required to discover an initial allosteric modulator. At the beginning, this approach led to serious disagreements within the community between “screening groups” and biologists about whether it is worth the effort to perform such screens and how to do them. Today, with several dozens of PAMs and negative allosteric modulators (NAMs) in clinical trials as a result of focused efforts, such discussions are largely over. X-ray structures of several types of receptors, including one of the most commonly used drug targets, GPCRs, also strongly suggest the presence of allosteric sites on monomeric, heterodimeric and homodimeric GPCRs25,26,27.

It is understood from the experience with numerous early screens that cellular assays where receptor occupancy by an orthosteric agonist can be measured are best suited to identify allosteric modulators. One needs to use a stable agonist in concentrations ranging between 20% and 30% of the maximal effect in the screening efforts (EC20 to EC30). Clearly, there is a room for identification of PAMs, while NAMs could be screened in the same setting using an orthosteric agonist at EC80 (Boxes 1 and 2). The work that discovered CYM250328 as a PAM of galanin receptor type 229 is described below in detail.

Efforts to find peptide receptor agonists: as exemplified for the search for galanin receptor agonists

Galanin is a 29 amino acid (aa) C-terminally amidated neuropeptide in pigs and rodents and a 30 aa long neuropeptide in humans30,31,32,33. It reacts with three types of GPCRs (galanin receptors 1–3, GALR1-3) (Figure 1) and GALR1 and GALR2 are involved in anticonvulsant activity33,34.

1) The pharmacophores and the orthosteric site of GALR1: The pharmacophores involved in the interaction with the receptor – ie, with its orthosteric site – were determined by two mutually complementary strategies: L-Ala substitution of the amino acids in galanin35 and site-directed mutagenesis of the galanin receptor residues suggested by modeling the agonist-receptor interactions36. These studies showed that the residues Trp 2, Asn 5, and Tyr 9 at the N-terminus of galanin (Figure 2A) were essential for binding to the surface residues of the galanin receptor, including His 264, His 267, Glu 271, Phe 115, and Phe 282 that constitute the orthosteric binding site37. Binding of galanin-29 or -30 to the native receptor occurs with high affinity (Kd 0.3–1 nmol/L) and high selectivity. It was also demonstrated that the shortest peptide, galanin 1–9, despite having all the pharmacophores, has a low affinity (μmol/L) and is peptidolytically unstable. The longer galanin 1–16 peptide has greater stability (half-life: 2–5 min in the circulation) and was employed in some studies, but it does not penetrate the blood-brain barrier (BBB)38. In addition, galanin 3–29 does not act as an agonist39, implying that inhibition of the dipeptidyl peptidase that cut the 1–2 residues (Gly-Trp) of galanin may augment the action of endogenous galanin. However, the attempt to find selective inhibitors of the dipeptidyl peptidase failed (Box 3).

2) Search for non-peptidic agonists: The distance between the two most distal pharmacophores, the N-terminal primary amino group and Tyr 9, is large for a small molecule scaffold to maintain. Nevertheless, peptides from a peptide library based on the pharmacophores were tested, and galnon was identified as a low molecular weight, systemically active galanin receptor agonist (Figure 2). It has a Kd of 1 μmol/L, exhibits no selectivity among the three galanin receptor subtypes, but is peptidolytically stable with a half-life of approximately 60 minutes and crosses the BBB40. This compound exhibited a remarkable and dose-dependent efficacy as an anticonvulsant, and thus reinvigorated the search for low molecular weight agonists and later for PAMs of the galanin receptor.

The pharmacophores were displayed on a cyclic scaffold by the Rebek group41, providing compound galmic (Figure 2). Galmic has a Kd of 1–2 μmol/L, possesses no receptor subtype selectivity, is peptidolytically stable with a half-life of approximately 120 min and crosses the BBB. This compound, like galnon, showed a dose-dependent and strong efficacy in several seizure models42.

Both galnon and galmic are capable of competing with galanin and could displace the endogenous peptide agonist from the orthosteric site. Their Kd and EC50 values correspond closely. Attempts to improve their affinities or to endow them with receptor subtype selectivity have not been pursued after the first series of SAR studies showed very narrow space for modifications. The desired affinity and pharmacokinetic properties for an orthosteric agonist of a central peptide receptor could not be reached with these compounds or close analogs of them. Other efforts to use the orthosteric site of galanin receptors are based on fatty acid derivatives of the peptide to enhance its permeability, to create a systemically active compound of the polar, short-lived neuropeptide, and to retain its pharmacophores43,44,45.

Search for PAMs of galanin receptors

The parallel development of multiple cellular assays in high-throughput format to search for GPCR ligands (agonists and antagonists) has provided us with the tools to discover PAMs. A general working paradigm of these efforts is summarized in Box 2. The advantages of PAMs over full agonists in binding to the orthosteric site are numerous. As discussed in the introduction, they are unlikely to cause receptor desensitization as some agonists do, they preserve the biological rhythm of the agonist action because they are only active when the endogenous agonist is released, and they can be of a completely different chemical structure as opposed to orthosteric site binders so that small molecules with desirable pharmacokinetic properties may be easier to find. However, there are two major concerns: the existence of a relatively stable orthosteric agonist to carry out the HTS assay reproducibly and lack of prior clues about which compound library to screen and to what structural classes these PAMs will belong. The access to two nonpeptidic, peptidolytically stable full agonists galnon40 and galmic41 that bind to the orthosteric site of GALR1 and GALR2 has solved the first concern above, although they are not of high-affinity or subtype-selective but can be applied at EC20 and EC80 concentrations (Box 3) to search for PAMs and NAMs in HTS using cell lines expressing GALR1 or GALR2 receptors.

In the case of the GALR2 receptor, IP3 production was monitored as the signal (Figure 1), a diverse chemical library was screened, and the hits were optimized to yield a PAM CYM2503 (Figure 2). This compound does not displace 125I-Tyr 9 galanin 1–29 from the orthosteric site (as galnon and galmic do), so it is a bona fide allosteric ligand. It enhances IP3 production elicited by sub-maximal concentrations of the orthosteric agonists galanin, galnon and galmic. Thus, CYM2503 is a PAM with receptor subtype selectivity for GALR2 only28.

The effects of CYM2503 are remarkably potent in the electroconvulsive shock and status epilepticus tests in vivo (Figure 3), where it was found to be as potent in reducing mortality in mice as the golden standard in the clinic, Keppra® (Levetiracetam). The animal experimentation data are sufficiently promising for initiating formulation work on this compound to improve its pharmacokinetic properties.


Since the first design-based, allosteric modulators for mGLuRs and GABAA receptors were developed approximately 10 years ago, we have acquired experience in identifying new members of this class of drugs. These practices confirmed that design-based allosteric modulators are a particularly attractive drug class when peptide receptor agonists are of low molecular weight and when derivation of the peptide fused with human serum albumin or with Fc antibody fragment, etc. is not applicable, as in the case of the peripherally active glucagon-like peptide-1 analogs used in diabetes therapy46,47. For glutamate, glycine and GABA receptors in the brain, we will see continued development of allosteric modulators of low molecular weight that can penetrate the BBB. Insights gained from recent advances in structural biology with availability of a dozen of ligand-bound GPCR X-ray structures will certainly accelerate these developments.

This manuscript is based on collaborations with Ulo LANGEL, Ed ROBERTS, Julius REBEK and Xiaoying LU. Several in vivo assays were carried out in other laboratories. We are most grateful to Claude WASTERLAIN, to the NINCDS for screening of anticonvulsants, and to Dale E Mais for critical review of this manuscript.

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Article Categories:
  • Review

Keywords: neuropeptide, galanin, GPCR, allosteric mudulation, CYM2503, anticonvulsant, drug screening.

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