delta OPIOID RECEPTOR SELECTIVE DRUGS FOR THE TREATMENT OF ALCOHOL USE DISORDERS
Currently three drugs have been approved by the federal drug administration to combat alcoholism: Revia (Naltrexone, a non-selective opioid antagonist), Campral (acamprosate, a NMDA receptor antagonist), and Antabuse (Disulfiram, an inhibitor of acetylaldehyde dehydrogenase). While each of these drugs can be efficacious in reducing ethanol consumption (by decreasing the rewarding effects of ethanol or by increasing the acetylaldheyde induced aversive effects), all of these drugs have clinical limitations and suffer from compliance issues. Thus, there is still a clear need for better drugs to help individuals curb their alcohol intake.
Opioid receptors and alcoholism.
The opioid receptor system is comprised of thee highly related receptors the mu, delta, kappa opioid receptors (MOR, DOR, KOR). Studies using knock out animals, have demonstrated that each of these receptors has a unique contribution to alcohol consumption. Mice with a disruption of the MOR drink less and show reduced preference for alcohol. Mice with a disruption of the KOR ligand dynorphin also drink less, but, paradoxically agonists at the KOR also decrease drinking, while antagonists enhance drinking. Mice disrupted for DOR show little difference in alcohol consumption when alcohol naïve, but show enhanced drinking and preference for alcohol once they have been drinking for some. Naltrexone, the antagonist drug used for the treatment of alcoholism in humans, is an antagonist at MOR, DOR and KOR. Because these three receptors have varied and perhaps opposing effects on drinking, a ligand such as naltrexone, that antagonizes multiple opioid receptors, may not be as efficacious at reducing ethanol consumption as a more selective ligand. Interestingly, two DOR subtypes (DOR1 and DOR2) can be pharmacologically distinguished in vivo. Recently we found that DOR1- and DOR2-selective ligands have opposing effects on ethanol consumption. Specifically, we found that DOR1 agonists and DOR2 antagonists decrease drinking while non-selective ligands produce no effect. Importantly, this could help explain the disappointing efficacy of naltrexone, a non-selective opioid antagonist that is currently approved to treat alcoholism. This is important for the development of a DOR selective drug, since only a DOR1 selective agonist or a DOR2 selective antagonist can decrease ethanol consumption. We subsequently identified that SNC80 a selective DOR agonist increases alcohol consumption and in this regard could be considered a DOR2-type ligand. This is in contrast with the DOR1 agonist TAN-67 that decreases consumption. Further studies revealed that these two agonist show distinct modulation of alcohol place preference.
DORs and anxiety
One of the drugs currently in clinical trials to treat alcoholism is the substance P neurokinin (NK1) receptor antagonist LY686017. It is thought that the efficacy of this drug is due, at least in part to the prevention of anxiety and craving in anxious alcohol dependent subjects. According to the National Institute of Mental Health, approximately 40 million US American adults (18% of the population) suffer from an anxiety disorder (Panic, obsessive-compulsive, post-traumatic stress and generalized stress disorder and social phobia). The individual and societal cost associated with anxiety disorders is extremely high. Importantly, people suffering from anxiety disorders are more susceptible to substance abuse and are at increased risk of suicide. Selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines (BZDs) are the two classes of drug most commonly used to treat anxiety disorders. SSRIs are generally well-tolerated; however, they take several weeks to take effect, and each SSRI is only effective in a subpopulation of patients, who cannot be identified prior to initiating treatment. BZDs are commonly prescribed to control anxiety “attacks;” however, they themselves are intoxicating and habit-forming. Importantly, BZDs can increase the palatability of ethanol and increase alcohol consumption. Thus, there is significant need for novel targets and treatments for anxiety disorders, especially for anxiety that is co-morbid with alcoholism. One target that is linked to anxiety is the DOR. Disruption of the gene encoding DOR or its endogenous ligand produces an anxious phenotype in mice, suggesting that DOR agonists should be anxiolytic. I found that DOR agonists are indeed anxiolytic and that previous alcohol exposure may enhance the potency of DOR1 selective ligands.
DOR subtypes and heteromerization
Knockout studies revealed that DOR1 mediated effects not only rely on the presence of DORs but also MORs, in contrast with DOR2 ligands whose effects where only abolished in DOR, but not MOR knockout mice. To assist in finding more DOR subtype selective ligands I developed a heteromer selective in vitro screening assay. Currently we are screening known DOR selective drugs and drug libraries to identify DOR subtype selective ligands that could function as lead candidate in our search for drugs that reduce alcohol consumption and (alcohol withdrawal induced) anxiety.
For this project we collaborate with Dr Markus Lill and Dr. Mark Cushman.
Relevant lab publications
Alongkronrusmee D, Chiang T, Van Rijn RM (2016). Involvement of delta opioid receptors in alcohol withdrawal-induced mechanical allodynia in male C57Bl/6 mice. Drug and Alcohol Dependence, 167, 190-198
Alongkronrusmee D, Chiang T, Van Rijn RM, Delta opioid pharmacology in relation to alcohol behaviors. Handb Exp Pharmacol, 2016
Van Rijn RM, DeFriel JN, Whistler JL, Pharmacological traits of delta opioid receptors: pitfalls or opportunities, Psychopharmacol, 2013, 228 (1): 1-18, PMC3679311
Van Rijn RM, Harvey JH, Brissett DI, DeFriel JN, Whistler JL, Novel screening assay for the selective detection of G protein-coupled receptor heteromer signaling, J Pharmacol Exp Ther, 334(1): 179-188, PMC3533407
Van Rijn RM, Brissett DI, Whistler JL, Distinctive modulation of ethanol place preference by delta opioid receptor selective agonists, 2012, Drug Alcohol Depend, 2012, 122(1-2):156-159 , PMC3279630
Van Rijn RM, Brissett DI, Whistler JL, Dual efficacy of delta opioid selective ligands for ethanol drinking and anxiety, J Pharmacol Exp Ther, 2010, 335 (1):133-139, PMC2957775
Van Rijn RM, Whistler JL. The delta-1 opioid receptor is a heterodimer that opposes the actions of the delta-2 receptor on alcohol intake, Biol. Psychiatry, 2009, 66:777-784, PMC2757485