Journal Article

Neuropeptide receptor ligands as drugs for psychiatric diseases: the end of the beginning?

Holsboer, Florian, Griebel, Guy

2012

Overview

Key Points The search for novel drugs for psychiatric disorders is driven by the growing medical need to improve on the effectiveness and side-effect profile of currently available therapies. The rapid advances in understanding the structure and regulation of genes encoding neuropeptides, the characterization of their receptors, the synthesis of non-peptide receptor ligands and the wealth of animal data have made neuropeptide receptors attractive therapeutic targets for the treatment of psychiatric disorders. However, clinical studies with synthetic neuropeptide ligands have been unable to confirm the promise predicted by animal studies. In this Review, we analyse preclinical and clinical results for neuropeptide receptor ligands that have been studied in clinical trials for psychiatric diseases, including agents that target the receptors for tachykinins, corticotropin-releasing factor, vasopressin and neurotensin, and suggest new ways to exploit the full potential of these candidate drugs. Although drugs targeting neuropeptide receptors have not met their expectations, we do not believe that the whole concept should be considered a failure. Among the most commonly noted reasons for the failure to successfully develop neuropeptide receptor ligands for psychiatric disorders is the poor predictivity of the animal models that have been used to screen these molecules. Drug selection based on data from animal models must be much more stringent and use a variety of models assessing different aspects of the disease. The future development of drugs targeting neuropeptide receptors also has to bear in mind the specificity of their mechanism of action. Genetic tests and biomarkers are needed to identify subgroups of patients in whom a specific neuropeptidergic mechanism accounts for the clinical condition and who would thus be anticipated to benefit from a specific drug intervention. A wealth of preclinical data on the role of neuropeptides in modulating behaviour has encouraged extensive efforts to target neuropeptide receptors for the treatment of psychiatric diseases, but so far clinical studies have not led to marketed drugs. This article analyses research on neuropeptide receptor ligands that have been studied in clinical trials, including agents that target the receptors for tachykinins, corticotropin-releasing factor and vasopressin, and suggests new ways to realize their full potential. The search for novel drugs for treating psychiatric disorders is driven by the growing medical need to improve on the effectiveness and side-effect profile of currently available therapies. Given the wealth of preclinical data supporting the role of neuropeptides in modulating behaviour, pharmaceutical companies have been attempting to target neuropeptide receptors for over two decades. However, clinical studies with synthetic neuropeptide ligands have been unable to confirm the promise predicted by studies in animal models. Here, we analyse preclinical and clinical results for neuropeptide receptor ligands that have been studied in clinical trials for psychiatric diseases, including agents that target the receptors for tachykinins, corticotropin-releasing factor, vasopressin and neurotensin, and suggest new ways to exploit the full potential of these candidate drugs.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/154/436/2387 / Animal models / Animals / Antipsychotic drugs / Biomedical and Life Sciences / Biomedicine / Biotechnology / Cancer Research / Clinical trials / Corticotropin-releasing hormone / Corticotropin-Releasing Hormone - physiology / Data processing / Drug Delivery Systems / Drug development / Drug therapy / Drugs / Health aspects / Humans / Ligands / Medicinal Chemistry / Mental disorders / Mental Disorders - drug therapy / Mental illness / Molecular Medicine / Neuropeptide receptors / Neuropeptides / Neurotensin / Neurotensin - physiology / Pharmaceuticals / Pharmacology/Toxicology / Physiological aspects / Psychotropic Drugs - therapeutic use / Receptors, Corticotropin-Releasing Hormone - physiology / Receptors, Neuropeptide - physiology / Receptors, Neurotensin - drug effects / Receptors, Neurotensin - physiology / Receptors, Tachykinin - physiology / Receptors, Vasopressin - drug effects / Receptors, Vasopressin - physiology / review-article / Side effects / Tachykinin / Tachykinins - physiology / Vasopressin / Vasopressins - physiology