Elsevier

The Lancet Neurology

Volume 2, Issue 8, August 2003, Pages 463-472
The Lancet Neurology

Review
Neuropeptides: opportunities for drug discovery

https://doi.org/10.1016/S1474-4422(03)00482-4Get rights and content

Summary

The role of peptides as signalling molecules in the nervous system has been studied for more than 30 years. Neuropeptides and their G-protein-coupled receptors are widely distributed throughout the body and they commonly occur with, and are complementary to, classic neurotransmitters. The functions of neuropeptides range from neurotransmitter to growth factor. They are present in glial cells, are hormones in the endocrine system, and are messengers in the immune system. Much evidence indicates that neuropeptides are of particular importance when the nervous system is challenged (eg, by stress, injury, or drug abuse). These features and the large number of neuropeptides and neuropeptide receptors provide many opportunities for the discovery of new drug targets for the treatment of nervous‐system disorders. In fact, receptor-subtype-selective antagonists and agonists have been developed, and recently a substance P receptor (neurokinin 1) antagonist has been shown to have clinical efficacy in the treatment of major depression and chemotherapy‐induced emesis. Several other neuropeptide receptor ligands are in clinical trials for various indications.

Section snippets

Discovery of neuropeptides

Mammalian neuropeptides were first discovered by extraction from large amounts (hundreds of kilos) of intestine or brain, or from thousands of hypothalamic fragments. In parallel, new peptides were isolated from other sources (eg, from frog skin9). Mutt and Tatemoto10 isolated further peptides by use of C‐terminal amidation as a chemical marker.

Rosenfeld and co-workers11 examined the gene for calcitonin, which is only expressed in the thyroid, and found that it encodes calcitonin-gene-related

Basic facts

The neuropeptides are 3–100 amino‐acid residues long and up to 50 times larger than classic neurotransmitters; they are smaller than regular proteins and have a less complex three‐dimensional structure. They contain more chemical information and possess several more recognition sites for the receptors than smaller neurotransmitter molecules. Consequently, there is a 1000 times difference in binding affinity between neuropeptides and classic transmitters (nmol/L vs μmol/L), the selectivity is

Neuropeptide receptors

Of particular importance to neuropeptide research was the identification of peptide receptors (table) and the development of pharmacological tools, particularly non‐peptide antagonists.26, 27 The first receptor—for substance K— was cloned in 1987.28 There are commonly several receptor subtypes for a given peptide ligand. Nearly all are seven‐transmembrane region, GPCRs; one exception is an ionotropic receptor for the non‐vertebrate tetrapeptide FMRFamide from the snail Helix aspersa;29, 30

Drug development

There are specific problems in trying to target peptidergic mechanisms for therapy. Peptides cannot be given orally because they are broken down by digestion. Moreover, for CNS neuropeptide receptors the main challenge is to make a compound that resists peptidase‐catalysed degradation and that can cross the blood–brain barrier (BBB). Non‐peptide ligands are most commonly found by random screening of large chemical libraries, and they are then chemically adapted to optimise their selectivity and

Neuropeptides and genetic manipulation

Neuropeptides can be studied easily in transgenic models45, 46 because the neuropeptides themselves are encoded in the genome, unlike classic neurotransmitters, such as catcholamine, GABA, acetylcholine, which are enzymatically synthesised. Hence, transgenic mouse strains that do not produce or that overexpress the neuropeptide can be generated to study the neuropeptide's effects. In fact, the deletion of specific receptors has been extensively used to determine which actions are mediated by

Diversity of neuropeptide functions

One of the principal driving forces of neuropeptide research in the early 1970s was the discovery, by Guillemin,48 Schally,49 and associates (Nobel Prize, 1976), that nearly all hypothalamic releasing factors are peptides; dopamine, which is the main prolactin inhibitory factor, is a non‐peptide exception. The neuropeptides are similar to the peptide hormones vasopressin and oxytocin in the magnocellular neurons, which project into the posterior lobe of the pituitary (de Vigneud, Nobel Prize,

Substance P

Neuropeptides have traditionally been of interest in pain transmission. 50 years ago, Fred Lembeck60 suggested that substance P is a pain transmitter. Lembeck's theory was proved by the findings of this peptide in small dorsal root ganglion neurons, of neurokinin 1 receptors on dorsal-horn-projection neurons, and of the distinct excitatory effects of substance P on dorsal‐horn neurons that could be blocked by specific antagonists. Studies in transgenic mice show that mice that lack either

Addiction

Antagonists of opioid receptors have been used in the treatment of diseases associated with drug addiction,85, 86, 87 including alcoholism.88, 89 Their effectiveness was recently confirmed in a large clinical trial.90 In fact, a relation between alcohol and neuropeptide intake91 has been further demonstrated. Neuropeptide Y knock‐out mice show increased ethanol intake,92 and the neuropeptide Y Y1 receptor is important for voluntary ethanol consumption.93 In intercross progeny obtained by

Seizure activity

Seizure activity causes pronounced region‐specific changes in expression of virtually every neuropeptide in the hippocampal formation.115, 116, 117, 118 For example, the neuropeptide Y system has seizure dependent regional and temporal variations of the peptide and its receptors in the hippocampal formation.119, 120 This regulation presumably serves to strengthen the antiepileptogenic effect of neuropeptide Y. For example, the increase in the peptide and its presynaptic Y2 receptors in granule

Control of food intake

CNS control of food intake is a fashionable research topic, and much of the focus in this area is on peptides. In fact, even if neuropeptides coexist with classic transmitters in these systems, little attention is given to the latter, perhaps with the exception of serotonin.130 This subject has been the focus of several recent review articles,131, 132, 133, 134, 135, 136, 137, 138, 139 and will therefore only be dealt with in brief.

Neuropeptides essential for feeding control are present in two

Other diseases

There is now evidence that mutations in genes that encode neuropeptides and their receptors may underlie some other diseases. Of special interest is the peptide hypocretin/orexin,15, 16 first assumed to be mainly involved in the control of food intake, but subsequently shown to be important for the sleep regulation.143, 144, 145 Narcoleptic dogs have mutations in the hypocretin/orexin receptor type 2 gene;146 deletion of receptors of this peptide in mice results in narcoleptic‐like

Conclusion

70 years after the discovery of substance P and after 30 years of focused and intense research on neuropeptides, the first “peptide” drug, a substance P antagonist, has been clinically tested for treatment of an important disease—major depression. The antagonist is as efficacious as selective serotonin reuptake inhibitors and has fewer side-effects. Moreover, this drug has now been approved by the US Food and Drug Administration for the treatment of emesis after chemotherapy. The slow progress

Search strategy and selection criteria

Data for this review were identified from the authors' own files and by searches of PubMed with the names of individual neuropeptides.

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