Developing a Vaccine Against Multiple Psychoactive Targets: a Case Study of Heroin
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CNS & Neurological Disorders - Drug Targets, 2011, 10, 865-875 865 Developing a Vaccine Against Multiple Psychoactive Targets: A Case Study of Heroin G. Neil Stowe1, Joel E. Schlosburg2, Leandro F. Vendruscolo2, Scott Edwards2, Kaushik K. Misra2, Gery Schulteis3, Joseph S. Zakhari1, George F. Koob2 and Kim D. Janda*,1 1Departments of Chemistry and Immunology, The Skaggs Institute for Chemical Biology and Worm Institute of Research and Medicine (WIRM), The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA 2Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037, USA 3Research Service, VA San Diego Healthcare System and Department of Anesthesiology, UC San Diego School of Medicine, USA Abstract: Heroin addiction is a wide-reaching problem with a spectrum of damaging social consequences. Currently approved heroin addiction medications include drugs that bind at the same receptors (e.g. opioid receptors) occupied by heroin and/or its metabolites in the brain, but undesired side effects of these treatments, maintenance dependence and relapse to drug taking remains problematic. A vaccine capable of blocking heroin’s effects could provide an economical, long-lasting and sustainable adjunct to heroin addiction therapy without the side effects associated with available treatment options. Heroin, however, presents a particularly challenging vaccine target as it is metabolized to multiple psychoactive molecules of differing lipophilicity, with differing abilities to cross the blood brain barrier. In this review, we discuss the opiate scaffolding and hapten design considerations to confer immunogenicity as well as the specificity of the immune response towards structurally similar opiates. In addition, we detail different strategies employed in the design of immunoconjugates for a vaccine-based therapy for heroin addiction treatment. Keywords: Heroin, 6-acetyl-morphine, morphine, addiction, drug dependence, immunoconjugate, treatment, therapy. 1. INTRODUCTION as the most harmful abused drug based on physical damage to the Heroin, (3,6-diacetylmorphine/diamorphine/morphine diacetate) user, the tendency to induce dependence and deleterious effects on was originally synthesized from morphine by the chemist Charles families, communities and society [11]. It is the illegal drug with Alder Wright in 1874 [1]. The pharmacological potency of heroin the highest mortality and emergency room visits according to the in frogs and rabbits was later examined by Dott and Stockman [2], United Nations [12], with medical care, loss of productivity, crime followed by a study in 1890 by the British Medical Association that and social welfare costs estimated at roughly $22 billion per year in found heroin was more effective in depressing the spinal cord and 1996 [10]. Heroin is frequently administered by injection, with respiratory center in frogs and rabbits with a weaker narcotic action heroin and other opiates accounting for 83% of hospital admissions [3]. The pharmacology of heroin was studied by the physician von for injection drug abuse in the United States in 1999 [13]. As such, Mering [4] (who discovered hypnotic barbiturates [5]), the chemists intravenous heroin use can be viewed as a driving force in the Hoffman and Eichengrun (who were instrumental in the discovery spread of HIV/AIDS, with an estimated ten percent of new cases of aspirin [6]), and Dreser [7] before being marketed as a cough worldwide attributed to injection drug abuse [14]. This situation is suppressant by the German chemical company Bayer. Although not further exacerbated in developing and transitional countries: in initially regarded as an addictive substance, the abuse properties of 1999, injection drug abusers accounted for 69% of HIV infections heroin quickly became apparent with intravenous use, particularly in China, 66% of AIDS cases in Vietnam and 82% of HIV/AIDS in the United States, where its use was restricted to prescriptions by cases in Central and Eastern Europe [15]. the Harrison Act in 1914 and banned outright in the United States in 1924 [7]. Heroin is currently regarded as a drug of abuse 2. HEROIN AND ITS METABOLISM included in the United Nations list of narcotic drugs under After intravenous injection of heroin, users describe an intense international control, but has not been completely outlawed for ‘rush’ followed by a prolonged feeling of tranquility, reduced medicinal use in some countries [8]. apprehension and euphoria lasting for several hours [16-18]. These Despite its potential usefulness in providing pain relief, heroin pharmacological effects are generally attributed to heroin’s action is a highly addictive substance with high negative costs and impact at opioid receptors in the brain, with the -opioid receptor on society. Heroin is abused in most countries worldwide, with an considered as the major target. In comparison with other drugs of estimated 8 million people (0.14% of the world’s population) using abuse such as nicotine [19], cocaine [20, 21] and methamphetamine heroin each year [9]. Even though heroin use makes up a small [22-24], heroin is generally regarded as a prodrug that acts through portion of total illegal drug use (less than 5%) [10], it was assessed its host of psychoactive metabolites that are more potent -opioid receptor agonists than heroin itself [25-27]. After injection, the half- life of heroin in humans is approximately 4 minutes before *Address correspondence to this author at the Departments of Chemistry and conversion to 6-acetylmorphine (6AM), a result of rapid enzymatic Immunology, The Skaggs Institute for Chemical Biology and Worm hydrolysis of heroin’s 3’ phenolic ester, predominately in the blood Institute of Research and Medicine (WIRM), The Scripps Research by erythrocyte acetylcholinesterase (AChE) [28]. The enzymes Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA; serum butyrylcholinesterase (BuChE) [29] and human Tel: (858) 784-2515; Fax: (858) 784-2595; E-mail: [email protected] carboxylesterase 1 [30] and 2 [31] (hCE1, hCE2) are also capable of hydrolyzing heroin’s 3’ ester. 6AM has a measured half-life of 1-/11 $58.00+.00 © 2011 Bentham Science Publishers 866 CNS & Neurological Disorders - Drug Targets, 2011, Vol. 10, No. 8 Stowe et al. approximately 22 minutes in humans before it is hydrolyzed to degree of analgesic potency in comparison with heroin. The morphine by hCE1 and hCE2 in addition to erythrocyte AChE [28, literature strongly suggests that heroin is a prodrug acting primarily 31]. In humans, morphine has a half-life of around 176 minutes, through its psychoactive metabolites [26], with 6AM being the and is further metabolized to the non-psychoactive morphine-3- causative agent for heroin’s acute psychoactive effects after glucuronide (M3G) and psychoactive morphine-6-glucuronide injection [27]. (M6G), each of which possess half-lives of approximately 276 and The fate of heroin and 6AM once across the BBB has been the 267 minutes, respectively (Fig. 1) [32]. In comparing area under subject of some debate. Thus, it was hypothesized in 1972 by curve concentrations for heroin and all of its major metabolites, Oldendorf et al. that after injection, heroin rapidly traverses the M3G is the major metabolite, followed by M6G, morphine, 6AM BBB and is hydrolyzed to 6AM and subsequently morphine [36]. and heroin [32]. It should be noted that while M3G is a heroin However, it was found by Soreq et al. in 1999 that the form of metabolite in humans, guinea pigs, mice and rabbits, M6G is only a acetylcholinesterase present in the brain did not significantly metabolite of heroin in humans, guinea pigs and rabbits, not rats or hydrolyze heroin or 6AM in vitro, leading to the hypothesis that mice [33, 34]. once inside the brain heroin and 6AM are protected from the rapid Of particular immunopharmacological interest with respect to enzymatic hydrolysis found in blood [28]. This hypothesis has been heroin and its psychoactive metabolites is that while they are all supported by the work of Andersen et al., who found much higher structurally similar to heroin, they vary in lipophilicity, and thus brain concentrations of 6AM in comparison to morphine after ability to cross the blood brain barrier (BBB). The two acetyl injection of heroin or 6AM in mice [45], and by Karinen et al., who groups present on heroin’s scaffold, in addition to heroin’s pKa of determined that heroin is more stable in brain than blood [46]. 7.6 [35], confer lipophilicity, making heroin readily capable of Thus, despite the original predictions of Oldendorf, recent research crossing the blood brain barrier (BBB) [36]. It has been suggested provides significant evidence that once across the BBB, heroin and that the brain uptake of heroin is controlled by the flow of blood 6AM are more resistant to the rapid enzymatic hydrolysis occurring into the brain [37], helping to create the intense pharmacodynamic in blood. effect felt by heroin users. This intense effect, or ‘rush’, is a major The acute effects of the highly lipophilic heroin/6AM can be contributing factor to the highly addictive nature of heroin, as well compared with the less lipophilic psychoactive heroin metabolites as other drugs of abuse [38-40]. Interestingly, previous research has morphine and M6G. With respect to morphine, the work of shown that decreasing the ‘rush’ felt after administration of cocaine Oldendorf et al. determined that 15 seconds after