Is there a future for neuropeptide receptor ligands in the treatment of anxiety disorders?

This review provides an overview of preclinical and clinical evidence of a role for the neuroactive peptides cholecystokinin (CCK), corticotropin rele asing factor (CRF), neuropeptide Y (NPY), tachykinins (i.e., substance P, n eurokinin [NK] A and B), and natriuretic peptides in anxiety and/or stress- related disorders. Results obtained with CCK receptor antagonists in animal studies have been highly variable, and clinical trials with several of the se compounds in anxiety disorders have been unsuccessful so far. However, f uture investigations using CCK receptor antagonists with better pharmacokin etic characteristics and animal models other than those validated with the classical anxiolytics benzodiazepines may permit a more precise evaluation of the potential of these compounds as anti anxiety agents. Results obtaine d with peptide CRF receptor antagonists in animal models of anxiety convinc ingly demonstrated that the blockade of central CRF receptors may yield anx iolytic-like activity. However, the discovery of nonpeptide and more lipoph ilic CRF receptor antagonists is essential for the development of these age nts as anxiolytics. Similarly, there is clear preclinical evidence that the central infusion of NPY and NPY fragments selective for the Y-1 receptor d isplay anxiolytic like effects in a variety of tests. However, synthetic no npeptide NPY receptor agonists are still lacking, thereby hampering the dev elopment of NPY anxiolytics. Unlike selective NK1 receptor antagonists, whi ch have variable effects in anxiety models, peripheral administration of se lective NK2 receptor antagonists and central infusion of natriuretic peptid es produce cleat anxiolytic like activity. Taken as a whole, these findings suggest that compounds targeting specific neuropeptide receptors may becom e an alternative to benzodiazepines for the treatment of anxiety disorders. (C) 1999 Elsevier Science Inc. All rights reserved.