ReviewBehavioral, biological, and chemical perspectives on targeting CRF1 receptor antagonists to treat alcoholism
Introduction
Each year, almost half of all American adults (47%) suffer from an addictive disorder (Sussman et al., 2011). Alcohol misuse alone has an annual prevalence of 10% (Sussman et al., 2011) and accounts for 10% of total disability in developed countries (Rehm et al., 2009). Most of the disability and cost to society results from alcohol dependence, or alcoholism, which has lifetime prevalence in the United States of more than 12% (Hasin et al., 2007). Available pharmacotherapies for alcoholism have only modest long-term efficacy and are underutilized (Heilig et al., 2011). Novel treatment options are needed. Here, we review the current state of therapeutically targeting corticotropin-releasing factor (CRF) systems to prevent alcohol dependence and relapse.
Brain and pituitary CRF1 receptors mediate many endocrine, behavioral, and autonomic responses to stress (Heinrichs and Koob, 2004). Accordingly, the pharmaceutical industry has sought to develop blood–brain barrier-penetrating CRF1 receptor antagonists for stress-related psychiatric conditions, including anxiety disorders and major depression (Holsboer and Ising, 2008, Koob and Zorrilla, 2012, Zorrilla and Koob, 2004, Zorrilla and Koob, 2010). Indeed, the search for CRF receptor antagonists began from the time that Vale and colleagues isolated the stress-secreted CRF peptide in 1981 (Vale et al., 1981). In addition to CRF, the CRF/urocortin (Ucn) system includes genes encoding three CRF paralogs (Ucn 1, Ucn 2, and Ucn 3) and two G-protein coupled receptors (CRF1, CRF2), with which the CRF/Ucn peptides interact (Fekete and Zorrilla, 2007). Extensive, previously reviewed preclinical data support the therapeutic potential of blood–brain barrier penetrating CRF1 receptor antagonists for different facets of alcohol dependence (Breese et al., 2011, Ciccocioppo et al., 2009, Heilig et al., 2010a, Heilig et al., 2010b, Heilig et al., 2011, Heilig and Koob, 2007, Koob and Zorrilla, 2010, Koob and Zorrilla, 2012, Le and Shaham, 2002, Logrip et al., 2011, Martin-Fardon et al., 2010, Shalev et al., 2010, Zorrilla and Koob, 2010). Here, we will focus on (i) recent developments in the medicinal chemistry of CRF1 receptor antagonists, (ii) the progress of specific small molecule CRF1 receptor antagonists in clinical trials, and (iii) issues related to the potential heterogeneity and pharmacogenomics of CRF1 receptor pharmacotherapy for alcoholism. The review is derived from our 2012 Behavior, Biology and Chemistry “Translational Research in Addiction” symposium in San Antonio, Texas.
Section snippets
CRF/urocortin system molecules
CRF1 and CRF2 receptors are class B1 (“secretin-like”) G-protein coupled receptors that share ∼70% sequence identity with one another. The CRF1 receptor exists in multiple isoforms (e.g., CRF1a–CRF1h), with the CRF1(a) subtype being the major functional isoform. In humans, the CRF2 receptor has three known membrane-associated functional subtypes – CRF2(a), CRF2(b), and CRF2(c). CRF peptide has preferential agonist activity for CRF1 vs. CRF2 receptors. Ucn 1 is a high-affinity agonist at both
CRF1 receptor antagonists in anxiety models
CRF1 receptor antagonists produce anxiolytic-like effects in animal models of anxiety. In rodents, CRF1 receptor antagonists reduced acoustic startle responding (Chen et al., 1997, Schulz et al., 1996), conditioned fear (Hikichi et al., 2000, Kikusui et al., 2000), shock-induced freezing (Weninger et al., 1999), and defensive burying behavior (Heinrichs et al., 2002, Richardson et al., 2008, Zhao et al., 2007a, Zorrilla et al., 2003). CRF1 receptor antagonists also produced anxiolytic-like
CRF1 receptor antagonists in withdrawal/negative affect models of alcohol dependence
The reviewed preclinical data suggest that extrahypothalamic CRF1 systems subserve some negative emotional states. Activation of CRF systems may therefore contribute to the withdrawal/negative affect stage of the addiction cycle. Individuals with high levels of innate anxiety or depression may be more likely to consume alcohol for its anxiolytic or dysphoria-relieving effects (Pohorecky, 1991). By reducing dysphoria, CRF1 receptor antagonists may help treat individuals who “self-medicate”
Pharmacophore and selectivity of nonpeptide CRF1 receptor antagonists
Almost all disclosed nonpeptide CRF1 receptor antagonists conform to a single pharmacophore. Prototypical compounds (Fig. 1) share one or two aliphatic top units that occupy a hydrophobic pocket of the receptor, a central mono-, bi-, or tricyclic ring core, and an orthogonal, conformation-stabilizing, di- or tri-substituted aromatic bottom group. Each ring core contains a putative proton-accepting ring nitrogen separated from the pendant aromatic by a one- or, more commonly, two-atom spacer.
Heterogeneity of alcohol use disorders between and within individuals
The effectiveness of medications for alcohol use disorders may vary both across individuals and also within individuals at different times (Heilig et al., 2010b, Heilig et al., 2011, Koob and Zorrilla, 2010, Logrip et al., 2011, Logrip et al., 2012). For example, treatments may be differentially effective for different diagnoses because of the different underlying biological and psychological mechanisms, and, for similar reasons, during different stages of the addiction cycle. Based on the
Concluding remarks
We briefly reviewed basic pharmacological and behavioral properties of small-molecule CRF1 receptor antagonists as well as their clinical trial status for psychiatric disorders. We discussed their potent effect in three main alcohol addiction-related behaviors in animal models: dependence-induced escalation of alcohol intake, negative emotional symptoms of acute and protracted withdrawal, and stress-induced relapse to alcohol seeking. These data provide a strong rationale for “translating”
Role of funding source
The research was supported by National Institutes of Health grants AA006420, DA02812, DK026741 and DK070118 as well as travel support from the Behavior, Biology and Chemistry: Translational Research in Addiction 2012 symposium. Funding for the BBC conference was made possible, in part, by R13DA029347 from the National Institute on Drug Abuse. The research of YS and MH is supported by the Intramural Research Programs of NIDA and NIAAA. The content is solely the responsibility of the authors and
Contributors
EPZ and YS wrote the first draft based on collective conceptual input of all authors at the symposium. All authors edited, substantively revised, are responsible for and approved the content of the submitted review.
Conflict of interest
EPZ is co-inventor on a patent for the composition and use of non-peptide CRF1 receptor antagonists (US20100249138). MH, YS and HdW have no conflicts of interest with the content of this review.
Acknowledgements
We thank Mary Gichuhi for administrative assistance. This is research publication number 21960 from The Scripps Research Institute.
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