Our focus on the pharmacogenetics of CRF₁ antagonists is simply because they are in clinical development

We recently reviewed accumulating evidence that pharmacotherapies for alcohol addiction will have to be personalized, with the genetic make-up of the individual probably being one of the key variables for identifying responsive patients (Pharmacogenetic approaches to the treatment of alcohol addiction. Nature Rev. Neurosci. 12, 670–684 (2011))¹. Corticotropin-releasing factor (CRF) receptor 1 (CRF₁) is an emerging treatment target for alcoholism that has a compelling preclinical validation. Findings that support this receptor as a candidate target have been obtained using systemic administration of CRF₁-selective non-peptide antagonists. The predictive validity of these observations does not rely on any assumptions about the nature of the endogenous ligand (or ligands) whose actions are blocked by this class of drugs. Owing to the existence of orally available, brain-penetrant molecules in this class that are also safe and well tolerated for human use, CRF₁ antagonists have recently entered clinical development for alcohol addiction. Functional genetic variation at the gene locus that encodes CRF₁ has therefore become of immediate relevance for personalizing treatments that target this receptor.

Giardino and Ryabinin (Corticotropin-releasing factor: innocent until proven guilty. Nature Rev. Neurosci. 14 Dec 2011 (doi:10.1038/nrn3110-c1))² point out the exquisite complexity of the CRF family of peptides and their receptors, which extend well beyond CRF₁ and may influence alcohol consumption in multiple ways. The Ryabinin laboratory has made important contributions to this literature³. Other data also suggest that activation of CRF receptor 2 (CRF₂) by one of its endogenous urocortin ligands or an analogue might result in effects on alcohol intake similar to those seen when CRF₁ is blocked⁴. These data predict that synthetic CRF₂ agonists with drug-like properties may have the potential to become medications for alcoholism, much like CRF₁ antagonists. Such a prediction is consistent with recent data indicating that urocortins, presumably through their ability to activate CRF₂, are required for effective recovery from stress⁵.

We share the hope that the discovery of urocortins and their CRF₂-mediated actions will ultimately lead to new opportunities for the development of treatments for addictive disorders. However, as Giardino and Ryabinin point out, no small molecules currently exist that target CRF₂ and are suitable for human use. Against that background, it is perhaps reasonable to focus a pharmacogenetic review on targets for which medications are actually in clinical development. CRF₁ is such a target, whereas CRF₂ is currently not. Giardino and Ryabinin argue that the slower development of CRF₂-targeted therapies is a result of the field neglecting them. The reality is, unfortunately, quite different. There is no lack of potentially attractive targets for alcoholism pharmacotherapies⁶. The main barrier to bringing forward novel pharmacotherapies is instead the difficulty in developing molecules that are suitable for human use. For reasons that are unclear, no non-peptide agonists for any member of the secretin family of G-protein-coupled receptors have been successfully developed. We certainly hope for breakthroughs in this area. Until those are achieved, however, we continue to believe patients are best served by focusing on targets with demonstrated potential for clinical development.