Current Topics in Medicinal Chemistry - Volume 11, Issue 9, 2011

Treatments for substance abuse disorders and improving the understanding of how drugs of abuse behave are important endeavors that still require medicinal chemistry approaches to solve. This special issue includes the discussion of some protein targets that are not well studied and that have no approved drugs specifically targeting them. Certainly, some of the areas discussed in this special issue are hot areas of drug development. The fact that there are still no approved medications in the United States to treat cocaine or methamphetamine abuse underscores the urgent need for drug discovery and development in these areas. Also, ways to mitigate opioid abuse are addressed in this issue. Finally, there are a couple of articles on the GABA system that can be linked to some of the consequences of drugs of abuse and disorders that are the results of drug abuse. This special issue begins with an article from Peter Crooks and Linda Dwaskin's groups at the University of Kentucky on analogs of the natural product, lobeline, as potential treatments for psychostimulant abuse. The targeting of VMAT2 is an interesting and promising area for medications development, particularly in the area of methamphetamine abuse. Next, and article from Chris McCurdy's lab at the University of Mississippi discusses targeting sigma receptors to attenuate the stimulant and rewarding effects of cocaine. These two articles address some recent targets with great potential in discovering and developing a drug for the treatment of cocaine or metehamphetamine abuse. Next, there are three articles involved with the opioid systems. First, Nurulain Zaveri from Astraea Therapeutics details targeting the Nocicpetin/Orphanin FQ receptor (NOP) for drug abuse medications. This target shows some interesting and unique potential for mitigating the effects of drugs of abuse. The second article comes from Susan Mercer and Andy Coop and details opioid analgesics and the P-glycoprotein (P-gp) efflux transporters. This is a review that deals with the contribution of the P-gp to analgesic tolerance and particulary how compound lacking P-gp substrate activity might be exploited. The final article in the opioid area comes from Jessica Adkins, Edward Boyer and Chris McCurdy and focuses on the natural product Mitragya speciosa (also known as Kratom) and its potential ability as a medication to alleviate opioid withdrawal syndrome. The last two articles in this special edition come from John Atack and detail the development of GABAA receptor subtypeselective modulators as either non-sedating anxiolytics or cognitive enhancers. These projects could result in drugs that would be potentially devoid of abuse potential as anxiolytics; and compounds that would have the potential to aid in cognitive deficits that may arise from several types of disorders. In summary, many years and millions of dollars have been spent targeting the dopamine system to attenuate drugs of abuse without much success. Currently, there are many novel targets being investigated that hold promise in the development of drugs to help in the treatment of substance abuse disorders. Although this issue only covers a few of these systems, it is clear that other important systems can be targeted as potential avenues for medications development.

The vesicular monoamine transporter-2 (VMAT2) is considered as a new target for the development of novel therapeutics to treat psychostimulant abuse. Current information on the structure, function and role of VMAT2 in psychostimulant abuse are presented. Lobeline, the major alkaloidal constituent of Lobelia inflata, interacts with nicotinic receptors and with VMAT2. Numerous studies have shown that lobeline inhibits both the neurochemical and behavioral effects of amphetamine in rodents, and behavioral studies demonstrate that lobeline has potential as a pharmacotherapy for psychostimulant abuse. Systematic structural modification of the lobeline molecule is described with the aim of improving selectivity and affinity for VMAT2 over neuronal nicotinic acetylcholine receptors and other neurotransmitter transporters. This has led to the discovery of more potent and selective ligands for VMAT2. In addition, a computational neural network analysis of the affinity of these lobeline analogs for VMAT2 has been carried out, which provides computational models that have predictive value in the rational design of VMAT2 ligands and is also useful in identifying drug candidates from virtual libraries for subsequent synthesis and evaluation.

Sigma receptors have been well documented as a protein target for cocaine and have been shown to be involved in the toxic and stimulant actions of cocaine. Strategies to reduce the access of cocaine to sigma receptors have included antisense oligonucleotides to the sigma-1 receptor protein as well as small molecule ligand with affinity for sigma receptor sites. These results have been encouraging as novel protein targets that can attenuate the actions of cocaine are desperately needed as there are currently no medications approved for treatment of cocaine toxicity or addiction. Many years of research in this area have yet to produce an effective treatment and much focus was on dopamine systems. A flurry of research has been carried out to elucidate the role of sigma receptors in the blockade of cocaine effects but this research has yet to yield a clinical agent. This review summarizes the work to date on the linkage of sigma receptors and the actions of cocaine and the progress that has been made with regard to small molecules. Although there is still a lack of an agent in clinical trials with a sigma receptor mechanism of action, work is progressing and the ligands are becoming more selective for sigma systems and the potential remains high.

Several studies show that the nociceptin receptor NOP plays a role in the regulation of reward and motivation pathways related to substance abuse. Administration of the NOP's natural peptide ligand, Nociceptin/Orphanin FQ (N/OFQ) or synthetic agonist Ro 64-6198 has been shown to block rewarding effects of cocaine, morphine, amphetamines and alcohol, in various behavioral models of drug reward and reinforcement, such as conditioned place preference and drug self-administration. Administration of N/OFQ has been shown to reduce drug-stimulated levels of dopamine in mesolimbic pathways. The NOP-N/OFQ system has been particularly well examined in the development of alcohol abuse in animal models. Furthermore, the efficacy of the mixed-action opioid buprenorphine, in attenuating alcohol consumption in human addicts and in alcohol-preferring animal models, at higher doses, has been attributed to its partial agonist activity at the NOP receptor. These studies suggest that NOP receptor agonists may have potential as drug abuse medications. However, the pathophysiology of addiction is complex and drug addiction pharmacotherapy needs to address the various phases of substance addiction (craving, withdrawal, relapse). Further studies are needed to clearly establish how NOP agonists may attenuate the drug addiction process and provide therapeutic benefit. Addiction to multiple abused drugs (polydrug addiction) is now commonplace and presents a treatment challenge, given the limited pharmacotherapies currently approved. Polydrug addiction may not be adequately treated by a single agent with a single mechanism of action. As with the case of buprenorphine, a mixed-action profile of NOP/opioid activity may provide a more effective drug to treat addiction to various abused substances and/or polydrug addiction.

Chronic clinical pain remains poorly treated. Despite attempts to develop novel analgesic agents, opioids remain the standard analgesics of choice in the clinical management of chronic and severe pain. However, mu opioid analgesics have undesired side effects including, but not limited to, respiratory depression, physical dependence and tolerance. A growing body of evidence suggests that P-glycoprotein (P-gp), an efflux transporter, may contribute a systems-level approach to the development of opioid tolerance. Herein, we describe current in vitro and in vivo methodology available to analyze interactions between opioids and P-gp and critically analyze P-gp data associated with six commonly used mu opioids to include morphine, methadone, loperamide, meperidine, oxycodone, and fentanyl. Recent studies focused on the development of opioids lacking P-gp substrate activity are explored, concentrating on structure-activity relationships to develop an optimal opioid analgesic lacking this systems-level contribution to tolerance development. Continued work in this area will potentially allow for delineation of the mechanism responsible for opioid-related P-gp up-regulation and provide further support for evidence based medicine supporting clinical opioid rotation.

Mitragyna speciosa Korth. (Rubiaceae) is a tree that is commonly found in Southeast Asia. Leaves from this tree have been traditionally been used for both their stimulant properties as well as an opium substitute. The tree/leaves are currently illegal in four countries, but is currently legal and widely available in the United States. To date over 40 compounds have been isolated from the leaves. The major alkaloid found within the crude extract, mitragynine, has been the subject of many pharmacological studies. In addition to the pharmacological studies, two total syntheses of mitragynine have been published as well as general structure-activity relationships (SARs) with respect to opioid activity.

The prototypic benzodiazepines, such as diazepam, are not only anxiolytic but also produce sedation. These effects are mediated by GABAA receptors containing either an α1, α2, α3 or α5 subunit at which the positive modulatory effects (i.e., agonist efficacy) of benzodiazepines are mediated via a specific benzodiazepine recognition site. Recent molecular genetic and pharmacological data point to α1-containing GABAA receptors as the “sedative” and α2- and/or α3- containing receptors as the “anxiolytic” subtype(s). Therefore, at Merck Sharp & Dohme attempts were made to identify subtype-selective compounds that modulate α2/α3 but not α1 receptor function with the prediction that such compounds would be non-sedating anxiolytics. The initial strategy for discovering such “anxioselective” compounds focussed on producing compounds with much higher affinity at the α2/α3 compared to α1 subtypes. The starting point for this approach was the triazolophthalazine series developed from a combination of a screening hit and a literature compound [1]. However, the maximum α3 versus α1 binding selectivity that could be achieved in this series was 12-fold and this was not considered sufficient for an appropriate in vivo pharmacological differentiation compared to non-selective compounds. Nevertheless, within this series compounds demonstrating (albeit to a limited extent) higher agonist efficacy at the α3 versus α1 subtype were also identified. This suggested that it might be possible to synthesize a compound with higher efficacy at the α2 and/or α3 compared to α1 subtypes, ideally with no efficacy at the latter subtype (i.e., a compound with subtypeselective efficacy). By changing the structure from a triazolophthalazine to a triazolopyridazine core, a number of either pharmacological tool compounds (L-838417, MRK-067 and MRK-696) or clinical development candidates (MRK-409 and TPA023) were identified. Encouraged by the success of this approach and the observation that the benzimidazole NS- 2710 had a modest degree of α3 versus α1 selectivity efficacy, a structurally-related class of imidazopyridines was also explored. The introduction of an additional nitrogen into the imidazopyridine core gave the imidazopyrimidine series which initially had issues with poor dog pharmacokinetics. However, this was resolved and resulted in the identification of the development candidates MRK-623 and MRK-898. A fluoroimidazopyridine was found to be a bioisostere of the imidazopyrimidine core and in this series the α3-selective tool compound TP003 was identified. The addition of a further nitrogen into the imidazopyrimidine core produced the imidazotriazine series, which yielded the clinical candidate TPA023B. Imidazopyrazinone and imidazotriazinone compounds offered no advantages over their respective imidazopyrimidine and imidazotriazine analogues. Additional pharmacological tool compounds were identified within the pyridine, pyrazolotriazine, pyridazine and pyrazolopyridone series highlighting the general feasibility of GABAA receptor subtype selective efficacy as a strategy for developing compounds with novel in vitro and in vivo profiles.

Benzodiazepine site agonists (such as diazepam) are well-known to impair cognition. Since benzodiazepines exert their effects via modulation of α1-, α2-, α3- and α5-containing GABAA receptors, the cognition-impairing effects of diazepam must be associated with one or several of these subtypes. Of these different subtypes, α5-containing GABAA receptors represent an attractive option as the “cognition” subtype based upon the preferential localization of these receptors within the hippocampus and the well-established role of the hippocampus in learning and memory. As a result, it is hypothesized that an inverse agonist selective for the α5 subtype should enhance cognition. For example, L-655708, a partial inverse agonist with 50-100-fold higher affinity for the α5 relative to the α1, α2 and α3 subtypes of GABAA receptors, enhanced cognitive performance in rats. Unfortunately, however, the pharmacokinetic properties of this compound prevented it being developed further. In order to try achieve binding selectivity in a series structurally distinct from the imidazobenzodiazepines, the group at Merck Sharp & Dohme commenced studies within the triazolopyridazine series. Although a degree of binding selectivity could be achieved (a maximum of 22-125-fold for α5 versus α1, α2 or α3, this approach was dropped in favour of a strategy to identify compounds with either a combination of selective affinity and selective efficacy or purely selective efficacy. With respect to the former, screening of the Merck chemical collection identified a novel, moderately α5 binding selective thiophene series and further optimization of this series produced MRK-536, which demonstrated a modest α5 binding selectivity (∼10-fold) as well as α5 efficacy selectivity. However, the structureactivity relationship within this and the analogous tetralone series proved unpredictable and these series were not pursued further. The success of the selective efficacy approach on the α2/α3-selective agonist project led a similar paradigm being adopted for the α5 project. The starting point for this strategy was the triazolopyridazine 3 which, like MRK-536, possessed a degree of both α5 binding and efficacy selectivity. By changing the core from a triazolopyridazine to a triazolophthalazine structure, α5 binding selectivity was lost but with subsequent optimization, compounds with the desired profile (low or antagonist efficacy at the α1, α2 and α3 subtypes and marked inverse agonism at α5-containing receptors) could be achieved, allowing the clinical candidate α5IA as well as the structurally-related pharmacological tool compound α5IA-II to be identified. By appending features of the prototypic α2/α3-selective triazolopyridazine L-838417 (t-butyl and 1,2,4 triazole groups) along with the isoxazole of α5IA to a pyrazolotriazine core, an additional clinical candidate, MRK- 016, was described. Finally, a degree of α5 efficacy selectivity was achieved the pyridazine series but metabolic instability within this chemotype limited its further optimization. Overall, these studies demonstrate the feasibility of adopting a selective efficacy approach in the identification of α5 selective GABAA receptor inverse agonists.