Pharmacological targeting of dopamine D3 receptors: Possible clinical applications of selective drugs

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Pharmacological targeting of dopamine D3 receptors: Possible clinical applications of selective agents Emilio Merlo Picha,n, Ginetta Collob a

Experimental Medicine CNS, Takeda Development Centre Europe, London, UK Department of Molecular and Translational Medicine, University of Brescia, Italy

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Received 15 November 2014; received in revised form 26 June 2015; accepted 14 July 2015

KEYWORDS

Abstract

D3-preferential DA agonist; D3-preferential D2/D3 antagonist; Selective D3 antagonist; Parkinson disease; Schizophrenia; Addiction; Therapy; Clinical trial

Dopamine D3 receptors have been pharmacologically engaged in humans since the development of the first antipsychotics and ergot-derivative dopamine (DA) agonists, even without knowing it. These agents were generally non-selective, developed primarily to target D2 receptors. In the last 10 years the understanding of the clinical implication of D3 receptors has been progressing also due to the identification of D3 gene polymorphisms, the use of more selective PET ligands such as [(11)C]-( +)-PHNO and the learning regarding the clinical use of the D3preferential D2/D3 agonists ropinirole and pramipexole. A new specific neuroplasticity role of D3 receptor regarding dendrite arborisation outgrowth in dopaminergic neurons was also proposed to support, at least in part, the slowing of disease observed in subjects with Parkinson's Disease treated with DA agonists. Similar mechanisms could be at the basis of the antidepressant-like effects observed with DA agonists when co-administered with standard of care. Severe adverse event occurring with the use of anti-parkinsonian DA agonists in predisposed subjects, i.e., impulse control disorders, are now suggested to be putatively related to overactive D3 receptors. Not surprisingly, blockade of D3 receptors was proposed as treatment for addictive disorders, a goal that could be potentially achieved by repositioning buspirone, an anxiolytic drug with D3-preferential antagonistic features, or with novel selective D3 antagonists or partial agonists currently in development for schizophrenia. At the moment ABT-925 is the only selective D3 antagonist tested in schizophrenic patients in Phase II, showing an intriguing cognitive enhancing effects supported by preclinical data. Finally, exploratory pharmacogenetic analysis suggested that ABT-925 could be effective in a subpopulation of patients with a polymorphism on the D3 receptor, opening to a possible personalised medicine approach. & 2015 Published by Elsevier B.V.

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Correspondence to: Development Centre Europe, 61 Aldwych, London, WC2B 4AE, UK. Tel.: +442031168550; fax: +442031168001. E-mail address: [email protected] (E.M. Pich).

http://dx.doi.org/10.1016/j.euroneuro.2015.07.012 0924-977X/& 2015 Published by Elsevier B.V.

Please cite this article as: Pich, E.M., Collo, G., Pharmacological targeting of dopamine D3 receptors: Possible clinical applications of selective agents. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2015.07.012

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E.M. Pich, G. Collo

1.

Introduction

Since its discovery in the early 90’s, dopamine (DA) D3 receptor has attracted the interest of pharmacologists. Intriguingly, often without knowing it, D3 receptor had been targeted well before its discovery by unselective antipsychotics, such as chlorpromazine or haloperidol, and by antiparkinsonian agents such as l-DOPA and the DA agonists, all initially developed to target D2 receptors (Hobson et al., 1999; Seeman, 2002). All these compounds are generally characterised by high affinities to both D2/D3 receptors, but developed mostly to deliver the dominant post-synaptic D2like pharmacologic effects (Seeman, 2007). In fact, given the relatively less conspicuous actions on motor behavior, until recently D3 receptors were thought to unsubstantially contribute to any therapeutic effect. With the cloning of D3 receptors (Sokoloff et al., 1990), the discovery and characterisation of selective or D3preferential compounds (Reavill et al., 2000; Millan et al., 2002) and a better understanding of D3 receptor biology, it was realized that the D3 receptor pharmacology was radically different from those of D2 receptors, suggesting a potential independent therapeutic role of D3 targeting (Joice and Millan 2002, Heidbreder et al., 2005, Sokoloff et al., 2006, Newman et al., 2012, Collo et al., 2014). In spite of a strong engagement of pharmaceutical and academic research activity, to date no selective D3 agonist or selective D3 antagonist is presently available for therapeutic use in humans. The evidence of this engagement is supported by the filing of 157 patents regarding novel D3 antagonists in the period 2008–2012 (Micheli and Heidbreder, 2013), the preferred indications being schizophrenia, Parkinson's Disease, substance use disorders, alcoholism, smoking cessation, diabetic renal damage and premature ejaculation. Recent data suggest also a possible role in neurocognitive disorders (Nakajima et al., 2013) and in mood disorders (Zarate et al., 2004, Leggio et al., 2013). Fortunately the pharmacopeia counts a series of nonselective compounds with “preferential” D3 activity. These compounds, if dosed properly, can be used to explore D3dependent pharmacology in human. According to a common view, a compound can be defined “preferential” for a given receptor when it binds in vitro with an affinity at least 10fold higher than that of the second-best target. For example, the ergot-derivative DA agonists of the first generation had similar in vitro affinity for both D2 and D3 receptors (e.g., lisuride, pKi D2 = 9.18 and pKi D3 = 9.55) while the DA agonists of the second generation are characterised by a higher affinity for D3 (e.g., pramipexole, pKi D2= 5.77 and pKi D3 = 7.98; ropinirole pKi D2= 6.03 and pKi D3= 7.43) (Millan et al., 2002). According to this model, by dosing in the low effective dose range, D3-preferential compounds would bind primarily to the D3 receptors, delivering specific pharmacodynamic effects. This is the case of the D3-preferential D2/D3 agonist pramipexole and ropinirole, successfully dosed in the low range in subjects affected by restless leg syndrome (Kushida, 2006; Manconi et al., 2011). Among DA antagonists or partial agonists, cariprazine has been positioning as D3-preferential atypical antipsychotic with a promising effects on negative symptoms (Caccia et al., 2013). The anxiolytic buspirone, already

explored for therapeutic use in addictive disorders (McRaeClark et al., 2009), was recently repurposed as preferential D3 antagonist with a different estimated effective dose (Kim et al., 2014; Le Foll et al., 2014). Finally, considering the compounds in early clinical development, strong hope is placed on the ABT-925, the only selective D3 antagonist in Phase II (Redden et al., 2011), while GSK598809, GSK618334 and ABT-614 are currently in Phase I. In this review we will attempt to summarize the present status of clinical targeting of D3 receptor in the development of potential therapeutic agents for disorders involving dysfunctional dopaminergic system, focusing on motor disorders, schizophrenia and addiction. The potential therapeutic role in cognitive and mood disorders will be briefly mentioned, suggesting recent reviews focused on these topics. Reference to preclinical and translational models will be kept at minimum, the key interest mostly being on human data. Excellent reviews on preclinical data and translational therapeutic hypothesis can be found in the literature (see also other articles of the current journal issue).

2. Dopamine D3 receptor in humans: Evidence of engagement by DA pharmacologic agents and the role of genetic variants The human D3 receptor is a 7TM G-protein coupled receptor whose gene is localised in 3q13.3 (Le Coniat et al., 1991), encoding a primary mRNA of more than 53,000 base pairs with six exons and five introns (Griffon et al., 1996). The translated human protein exhibits 78% homology with the rat D3 receptor, but differs in that there is a deletion of 46 residues in the 3rd intracellular loop (Giros et al., 1989). Its expression and localisation in human brain was studied in post-mortem tissues using both in situ hybridisation and receptor autoradiography for selective D3 ligands, showing an enriched expression in basal ganglia, in particular globus pallidus (Landwehrmeyer, et al., 1993; Murray et al., 1994).

2.1.

Neuroimaging

D3 receptors were recently visualised in vivo using as PET ligand [11C]-( + )-PHNO that recognises also D2 high-affinity receptors. When [(11)C]-( + )-PHNO was challenged with the selective D3 antagonists ABT-925 (Graff-Guerrero et al., 2010) and GSK598809 (Searle et al., 2010) significant displacements were consistently observed in the regions of substantia nigra and ventral tegmental area (SN-VTA) as well as in globus pallidus. Further anatomical assessment indicated that the fractions of [(11)C]-( + )-PHNO binding attributable to D3 receptors were 100% in the SN-VTA and in the hypothlamus, 60–75% in globus pallidus and ventral pallidum, and 50% or lower in caudate-putamen (Tziortzi et al., 2011). These results were somewhat at variance with what expected from studies in rodent, the ventral striatumnucleus accumbens being the richest D3 receptor region together with olfactory tubercles (Sokoloff et al., 1990). This imaging profile points to a critical role of SN-VTA and hypothalamus in mediating pharmacologic effects of D3 compounds. In other words, targeting the circuits involved in schizophrenia, addiction and motor control via D3

Please cite this article as: Pich, E.M., Collo, G., Pharmacological targeting of dopamine D3 receptors: Possible clinical applications of selective agents. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2015.07.012

Pharmacological targeting of dopamine D3 receptors receptors in humans seems different from what proposed in animals, questioning some translational propositions. A recent study using dual-modality PET-MRI in healthy volunteers has explored the relationship between D3 receptor expression as measured with [(11)C]-( + )-PHNO and functional connectivity. High D3 receptor levels in SN-VTA were associated with reduced functional connectivity between orbitofrontal cortex and networks implicated in cognitive control and salience processing. The opposite pattern was observed in subcortical reward circuitry, where amygdala is located, and the “default mode” network, which showed greater connectivity with orbitofrontal cortex in individuals with high D3R availability (Cole et al., 2012). Unpublished exploratory observations from the same group using a similar dual-modality approach (Beaver, Rabiner, Merlo Pich et al., study NCT00814957 at clinicaltrial.gov) provided information about the existence of a direct proportionality between individual levels of D3 receptor in SN-VTA and increased fMRI BOLD signal in the amygdala observed during a monetary incentive task. Interestingly, administration of the selective D3 DA antagonist GSK618334 resulted in a significant attenuation of amygdala activation as well as reduction of [11C]-( + )-PHNO binding potentials in the SN-VTA region. When the changes in [11C]-( + )-PHNO binding potentials in the SN-VTA region was correlated with BOLD change in the whole brain during a “money win” outcome event, the strongest correlation was found again in the amygdala. These data are in agreement with a role for D3 receptor in processing reward signals and motivation.

2.2.

Pharmacogenetics

Humans carry functional genetic variant in the D3 receptor. The most commonly studied polymorphism is the serine-toglycine substitution at amino acid position 9 (Ser9Gly, rs6280TC). In vitro the Gly allele displays a higher affinity for DA of heterologously expressed human D3 receptors and a more robust intracellular signal than the Ser allele (Jeanneteau et al., 2006). This biochemical difference could potentially drive behavioural differences in the efficiency of DA system activations, impacting on reward and motor functions, as recently proposed by Savitz et al. (2013). The Ser9Gly is a common variant, initially associated with the development of Tardive Dyskinesia (Lerer et al., 2002) and present in about 40–50% of the population. Growing evidence suggests a potential role for Ser9Gly polymorphism in determining response to pharmacologic targeting of D3 receptors. For example, in The Netherlands' GROUP study performed on 329 Caucasian patients, antipsychotic treatments were found more effective in improving psychotic symptoms in Gly carriers than Ser/Ser carriers (Vehof et al., 2012). This is in line with an initial metaanalysis showing better outcome to clozapine treatment in Gly-carriers, but these results were only partially confirmed in a recent and larger multi-ethnic metanalysis (Hwang et al., 2010). In another study Gly-carries with schizophrenia were also found more responsive to olanzepine in a controlled clinical trial, showing greater positive symptom remission in 39% of subjects with Gly/Gly and Gly/Ser genotypes vs. 14% subjects with Ser/Ser genotype (Adams et al., 2008). However, negative studies can be also found in

3 the literature. In a study assessing clinical responsiveness to risperidone in a Chinese cohort, no association with any genotype was found (Xuan et al., 2008). Therefore caution regarding generalisation of these observations is recommended. Interestingly, in a recent trial using the DA agonist pramipexole, clinical response rates in subjects with Parkinson Disease diagnosis were significantly higher in the Ser/ Ser group (60%) than in the group containing the Gly allele (13%). These results suggest a DA agonist-mediated effect on those subjects with less sensitive D3 receptor, the Ser/ Ser. These results are complementary to those reported with antipsychotics, whose primary blockade of D3 receptors in subjects with the Gly genotype should reduce an excessive D3-mediated neurotransmission putatively present in subgroups of patients with schizophrenia. This view can help the interpretation of the results of a recent clinical trial performed in subjects with exacerbation of schizophrenia using the selective D3 antagonist ABT-925 (Bhathena et al., 2013). While the study failed to show significant treatment effects, a signal of efficacy was observed in the Gly-carriers exposed to the highest dose of ABT-925 (see next paragraph). If confirmed in other trials, the D3 receptor Ser9Gly genotype could become a useful predictive biomarker to inform about which sub-group of patients will eventually better respond to treatment.

3. D3-preferential and D3-selective DA antagonist as possible treatment for schizophrenia, addiction, compulsive behavior and cognitive disorders 3.1.

Schizophrenia

The preferential blockade of D2 receptors in caudateputamen and ventral striatum produced by antipsychotics such as haloperidol, risperidone or olanzepine is associated with dose-dependent sedation, reduced reaction time to stimuli, reduction of spontaneous motor behaviour, rigidity, akathisia, blunting of emotional response that are observed in the majority of the subjects exposed. Conversely, studies in Phase I with the selective D3 antagonist GSK598809 do not report the same profile: headache and somnolence were the most common adverse events, observed in a minority of subjects, with no sedation or extrapiramidal symptoms (te Beek et al., 2012). These data parallel preclinical findings, reporting for D3 antagonist no effects on spontaneous locomotion or catalepsy at high doses, at variance with most antipsychotics. Interestingly, selective D3 antagonists are not effective in animal models developed to assess antipsychotic potential, such as amphetamine induced locomotion or active avoidance tests. However, selective D3 antagonists affect the firing of dopaminergic neurons in the VTA in a way similar to atypical antipsychotics and enhance DA and acetylcholine release in prefrontal cortex (Millan et al., 2007). In contrast to antipsychotics, D3 antagonists can improve a series of social and cognitive behaviours in rodents, including executive function, which are particularly impaired in patients with schizophrenia negative symptoms (Gross et al., 2013).

Please cite this article as: Pich, E.M., Collo, G., Pharmacological targeting of dopamine D3 receptors: Possible clinical applications of selective agents. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2015.07.012

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E.M. Pich, G. Collo

Atypical antipsychotics generally show in vitro high affinity for D2 and 5-HT2 receptors and less, but still high, for D3 receptors. However, it is unclear if the blockade of D3 receptor is contributing to the actual antipsychotic efficacy, i.e., reducing positive symptoms of schizophrenia. When D3 receptor displacement was studied in stable schizophrenic patients receiving antipsychotics, high occupancy was observed in dorsal striatum with both [(11)C]-( + )-PHNO and [(11)C]raclopride, the latter a D2-preferential ligand that recognise low affinity D2 receptors. Interestingly, while evidence of striatal displacement of both PET ligands was obtained, no displacement of [(11)C]-( + )-PHNO was shown in the globus pallidus. Interestingly, in this brain area displacement of [(11)C]-( + )-PHNO was obtained when the same subjects were exposed to a single dose of the D3preferential D2/D3 agonist pramipexole, suggesting that clozapine, risperidone or olanzapine may not be engaging these D3 receptors at the therapeutic doses considered (Graff-Guerrero et al., 2009). 3.1.1. Cariprazine A compound in development for schizophrenia and bipolar depression is cariprazine (RGH-188), currently poritioned as D3-preferential D2/D3 partial agonists (Kiss et al., 2010; Caccia et al., 2013). Cariprazine has a pKi for D3 = 10.1 and for D2= 9.3, with affinities for 5-HT2a and 5-HT2b similar to D2 receptor. Partial agonists are known to produce antagonist-like effects without blocking completely the receptor functions. Recent preclinical studies showed that cariprazine can produce both pro-cognitive and antianhedonic effects in rats (Papp et al., 2014), suggesting possible clinical applications in schizophrenia negative symptoms. Preliminary reports form randomised clinical trials indicated significant differentiation from placebo in both PANSS-positive and -negative symptoms, with insomnia, extrapyramidal symptoms, sedation and akathisia as most common adverse events (Caccia et al., 2013). However, while significant clinical improvements were reported at low doses (at which selectivity for D3 receptor engagement is more likely), the distribution of extrapyramidal symptoms (most likely D2-mediated) according to the dose has not been communicated. 3.1.2. ABT-925 ABT-925 is currently the only novel selective D3 antagonists in development for schizophrenia that was tested in patients. A randomised, double blind, placebo controlled, parallel group study was performed in 155 patients to assess safety tolerability and clinical effects in subjects with exacerbation of schizophrenia. Subjects were randomized in 3 groups, placebo, 50 mg and 150 mg ABT-925. The results showed no difference in the PANSS scores when compared with placebo at any concentration, suggesting an insufficient receptor occupancy due to the low doses selected (Redden et al., 2011). Data from the same study were reanalysed using the Ser9Gly D3 receptor polymorphism to identify a sub-population. The effect of Ser9Gly genotype on response to ABT-925 was examined in 117 subjects by associating the genotype Ser/Ser versus Gly to changes of PANSS clinical score from baseline to study-end. Significant genotype-by-treatment interaction was observed, with an

increased effect in the clinical outcomes of patients treated with ABT-925 150 mg who carried the Gly allele (Bhathena et al., 2013). This result suggest that a sub-population of patients with a the Gly genetic variant on amino acid 9 of the D3 receptor could better respond to agents that selectively reduce D3 receptor activity. However, to our knowledge, direct evidence of in vitro increased effects of ABT-925 to the human D3 receptor variant carrying the Gly polymorphisms is still missing.

3.2. Drug addiction and compulsive beahvior disorders In this chapter we review the evidence supporting the potential use of preferential D3 or selective D3 antagonists for the indication of substance-related and addictive disorders (SRAS) as described in DSM-5, which include disorders such as gambling, alcoholism, tobacco smoking, marijuana smoking, heroin addiction, cocaine and methamphetamine misuse including food craving (Volkow and Wise, 2005). All these disorders are characterised by either partially satisfactory treatments or no treatment at all. Preclinical findings point to compelling evidence in rodents and nonhuman primates for the attenuation of drug-seeking behavior and relapse to drug-taking behavior after a period of abstinence using selective D3 antagonists or D3 partial agonists (Heidbreder et al., 2005, Newton et al. 2012) In our search for recent clinical trials, two approaches were used: (1) repurposing of non-selective antagonists with preferential D3 antagonism, or (2) assess selective D3 antagonists in Phase I. In the first group buspirone, a marketed anxiolytic, was identified as a potential candidate on the basis of its high affinity for the D3 receptor (but also for 5-HT1A and D2). Recent data in non-human primates indicate attenuating effects of buspirone on drug-taking relapse in abstinent animals (Newton et al. 2012). In the second group are the selective D3 antagonist GSK598809, GSK6183334 and ABT-614 currently in Phase I. A search into the clinicaltrial.gov database was performed to identify human studies implementing D3 antagonists, by entering the key words “dopamine D3 receptor antagonist”, “buspirone”, “GSK598809”, “GSK6183334”, “ABT-614”. A total of 75 studies were identified, 16 of them were related to SRAS disorders or including since exploring D3 receptor occupancy using PET. They are summarised in Table 1. 3.2.1. Buspirone In ‘90 s the D3-preferring D2/5HT1A antagonist buspirone was studied in alcoholics and found to reduce anxiety, in particular during withdrawal (Bruno, 1989; Malec et al., 1996). Rose et al. (2003) studied the effects of buspirone on opiate withdrawal in chronic opiate users under methadone treatment. During 9 days of discontinuation from methadone, a daily treatment with buspirone (30 mg/day) significantly reduced the Objective Opiate Withdrawal Scale score when compared to placebo. Effects of buspirone were also observed in small trials testing cocaine users (Giannini et al., 1993; Moeller et al., 2001). A large multicentric BRAC study (NCT01641159) aimed to reduce cocaine consumption in chronic users (Winhusen et al., 2012) recently started

Please cite this article as: Pich, E.M., Collo, G., Pharmacological targeting of dopamine D3 receptors: Possible clinical applications of selective agents. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2015.07.012

Pharmacological targeting of dopamine D3 receptors

Table 1

5

Human studies with D3R antagonists on addiction (from 2003 to 2014).

clinicaltrial. Drug gov

Study pop.

Study title

Site

Status

NCT01699828 [11C]PHNOBuspirone NCT01188967 GSK598809

Healthy volunteer

PET study exploring D3R occupancy by Buspirone

University of Toronto

Recruiting

Massachussets General Hospital

Recruiting

NCT01641159 Buspirone

Cigarette smoker

A double-blind, placebo-controlled, parallel group design trial to study the effects of GSK598809 added to cognitive behavioural therapy and nicotine replacement therapy for prevention of early relapse to smoking. Cocaine users Relapse-prevention in adults with cocaine dependence (BRAC)

NCT01267292 Buspirone

Chronic cocaine users

NCT00875836 Buspirone

Marijuana users

NCT01639157 Buspirone

Chronic cocaine users Methampetamine abusers Chronic cocaine users

NCT01843205 Buspirone

NCT01267292 Buspirone

NCT00814957 [[11C]PHNO GSK6183334 NCT00788801 [[11C]PHNO ABT614 NCT00468806 [11C]-PHNO GSK598809 NCT1039454 GSK598809

NCT00360191 Buspirone

NCT00149617 Buspirone

NCT00605241 GSK598809

–

Healthy volunteers

University of Cincinnati

Active, not recruiting Randomized, double blind, placebo controlled, University of Texas, Recruiting parallel group trial to investigate the Houston psychopharmacology of Buspirone in cocaine dependence Randomised, double-blind, placebo controlled University of South Recruiting parallel group trial to assess the effect of Carolina Buspirone on marijuana users exposed to contingent management and motivation enhancement therapies Impact of Buspirone maintenance of the University of Recruiting reinforcing effects of cocaine Kentucky Buspirone as a candidate medication for University of Recruiting treatment of methampetamine abusers. Kentucky Randomized, double blind, placebo controlled, University of Texas, Recruiting Houston parallel group trial to investigate the psychopharmacology of Buspirone for cocaine dependence PET study exploring D3R occupancy of GSK CIC London Completed GSK6183334

Healthy volunteers

PET study exploring D3R occupancy of ABT-614 Abbot labs

Completed

Healthy volunteers Obese subjects with food craving/ binge Chronic marijuana users Chronic marijuana users

PET study exploring D3R occupancy of GSK598809 Randomised placebo controlled two-period crossover trial to investigate the effect of a single dose of GSK598809 on fMRI activation and behavioural response to food reward Randomised, double-blind, placebo controlled parallel groups trial oto study the effects of Buspirone in marijuana dependence Randomised, double-blind, placebo controlled parallel groups trial of to study the effects of Buspirone and motivational enhancement for treatment of marijuana dependence. Randomized, double-bind, placebo controlled, two-way crossover trial to investigate the effects of a single dose GSK598809 in modulating nicotine reward and craving PET study exploring D3R in abstinent alcoholics

GSK CIC London

Completed

University of Cambridge & Imperial College London University of South Carolina

Completed

University of South Carolina

Completed

PennState University, Philadelphia

Completed

Imperial College London

Completed

Chronic tobacco smokers

[11C]–PHNO Alcohol GSK598809 dependent Subjects NCT00326235 Buspirone

Randomised double-blind placebo controlled parallel group trials to study the effects of

Completed

Completed

Please cite this article as: Pich, E.M., Collo, G., Pharmacological targeting of dopamine D3 receptors: Possible clinical applications of selective agents. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2015.07.012

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E.M. Pich, G. Collo

Table 1 (continued ) clinicaltrial. Drug gov

NCT02132832 Buspirone

Study pop.

Study title

Site

Status

Heroin dependent subjects Marjuana users

Buspirone on opiate withdrawal in subjects with heroin dependence

VA New York Harbour, Brooklyn, NY The University of Texas Health Science Centre, Houston

Recruiting

Randomised double-blind placebo controlled parallel group trials to study the effects of Buspirone on stress and attentional bias in marijuana users

recruitment in USA. Buspirone effects on marijuana dependence were also investigated (McRae-Clark et al., 2009). Participants received either buspirone (30–60 mg/day, n= 23) or placebo (n =27) for 12 weeks, buspirone showing 18% more negative urine drug screenings vs. placebo. A recent neuroimaging study in monkey indicates D3 receptor occupancy using buspirone (Kim et al., 2014). Interestingly, selective D3 receptors engagement was observed only after oral dosing, while intramuscular administration was engaging also the D2 receptors. This fact was seen as indicative that buspirone metabolites generate by the first passage through the liver could be the actual active moiety. The initial data suggest the use of doses much higher than those used for anxiety. This observation, still preliminary, is opening the way to a possible further exploration of the use of buspirone-like compounds in addiction. This is of relevance, since a recent Chocrane metanalysis suggested that buspirone may not the most promising treatment option (Marshall et al., 2014). This analysis casts some doubt about the possible use of buspirone in drug dependence, while novel data from other trials currently in progress are awaited (i.e., NCT00360191 and NCT00875836 on clinicaltrial.gov). 3.2.2. GSK598809 Among the new selective D3 antagonists, GSK598809 was studied using a translational paradigm linking preclinical data obtained in rodents (or primates) with data obtained in human smokers within the context of a pharmacokinetic– pharmacodynamic (PK–PD) model aimed to identify the effective clinical dose (Mugnaini et al., 2013). A dose occupying about 75% of D3 receptors and effective in fully blocking the conditioned place preference for nicotine in rats was selected for a clinical study in human smoker volunteers. The calculated dose was only capable to transiently attenuate craving for cigarette in human smokers after an overnight abstinence without affecting other behavioural parameters and slightly increasing tobacco consumption, possibly as post-dosing compensatory effect (study NCT00605241). This discrepancy indicates a possible limitation in the assumptions of the model used to translate preclinical data in humans, possibly suggesting the need of higher exposure in human tobacco smokers. Other pharmacodynamic effects of GSK598809 were studied in obese individuals with binge eating using doses estimated to engage more than 75% D3 receptor occupancies. In study NCT1039454, GSK598809 reduced the attentional bias for highly palatable food of obese individuals,

but only in those subjects who reported low-restrained emotional eating, not affecting high-restrained eaters (Nathan et al., 2011). Interestingly, single dose GSK598809 also affected the approach responses to food cues in obese individuals, suggesting a reduction in the motivational attractiveness of food (Mogg et al., 2012). However, the food image-induced activation of the salience circuit in the brain of obese individuals, as measured with fMRI, was not affected by GSK598809 (Dodds et al., 2012). Currently, chronic GSK598809 is tested as add-on to behavioural therapy and nicotine patch replacement therapy for prevention of early relapse to smoking in severe chronic smokers (NCT01188967). The potential cardiovascular liability of GSK598809 at high doses has required the inclusion of an ambulatory monitor for each patient, increasing the hurdle of recruiting. The study should deliver results by 2015.

3.3.

Cognitive disorders

Converging findings, well summarised by Nakajima et al. (2013), indicate that D3 receptor blockade may also enhance cognition, including memory, attention, learning, social recognition and executive function. In human, while potential worsening effects of D3-preferential DA agonists were reported in a series of small studies (Nakajima et al., 2013), improved executive function and emotion recognition was found in schizophrenic individuals with the G allele of the DRD3 Ser9Gly polymorphism when daily dosed with the D3 selective antagonist ABT-925 (Gross et al., 2013). It is recognised that these are only initial findings; if confirmed, the potential impact of D3 antagonists in disorders such as dementia and cognitive impairment associated with schizophrenia could be of relevance, in particular in those carrying at-risk genotypes for dopaminergic hypofunction.

4. D3-preferential DA agonists as treatment for Parkinson's disease, restless leg syndrome and mood Disorders DA agonists are synthetic compound develop to mimic DA effects. Initially unselective ergot-derivative (e.g., bromocriptine, lisuride), they became more selective in targeting specifically D2/D3 receptors; ropinirole, pramipexole and rotigotine representing the second generation DA agonists for treatment of Parkinson Disorder (PD) (Connolly and Lang, 2014). Interestingly, the use of low dose D3 preferential DA

Please cite this article as: Pich, E.M., Collo, G., Pharmacological targeting of dopamine D3 receptors: Possible clinical applications of selective agents. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2015.07.012

Pharmacological targeting of dopamine D3 receptors agonist was successfully extended to restless leg syndrome (as reviewed in Ondo (2014)) and explored as co-treatment in mood disorders (reviewed in Liggio et al. 2013).

4.1. Parkinson disease: Possible neurotrophic-like effects of D3 receptor activation

7 move and periodic limb movements (Kushida, 2006; Manconi et al., 2011), suggesting a critical and specific role for D3 receptors in this disorder whose pathogenesis is still unclear (Ondo, 2014).

4.3. While the D2-mediated DA agonist effect was seen as critical in normalising motor function in subjects with PD, the role of the D3 receptor activation has been considered ancillary for years. Joyce and Millan (2007) proposed D3 receptor as key mediator for the protective and restorative effect of the DA agonists on dopaminergic neurons. This proposal was also based on the evidence that ropinirole and pramipexole slow the loss of dopaminergic cell terminals (and neurons) as measured using either F-DOPA PET or 123I-beta-CIT SPECT upon long-term administration to patients with PD when compared with l-DOPA treatment (Clarke and Guttman, 2002; Whone et al., 2003). The neurorestorative effects of D3-preferential D2/D3 agonists were observed in lesion animal models, where chronic administration restores the dopaminergic nigrostriatal pathway in rats previously damaged with the neurotoxin 6-OHDA via neurite outgrowth and increase of size and number of dopaminergic neurons (Van Kampen and Eckman, 2006). Similar neurotrophic-like effects were produced by D3-preferential D2/D3 agonists added in vitro to primary cultures of dopaminergic neurons from the mouse mesencephalon. The activation of D3 receptors triggered the specific phosphorylation of MEKERK and PI3K-Akt-mTORC1 intracellular signalling, both critical pathways for dendrite and soma size growth (Beom et al., 2004; Collo et al., 2008). The validity of D3-mediated effects was controlled using preparations from D3 KO mice, selective D3 antagonists and intracellular kinase inhibitors leading to a blockade of the structural plasticity enhanced by the D3preferential D2/D3 agonist (Collo et al., 2008, 2014). These observations, complemented by the hypothesis that l-DOPA can accelerate the loss of dopaminergic neurons via production of free radicals from DA metabolites (Lipski et al., 2011), further support use of D3-preferential D2/D3 agonists as first-line monotherapy for Parkinson Disorder treatment. Another reason for using DA agonists in treatment of PD early stage is the evidence of lower incidence of developing dyskinesia. Accordingly, chronic treatments with DA agonists were associated with 87% reduced occurrence of dyskinesia in later stages of the disease when compared with subjects treated with l-DOPA (Chondrogiorgi et al., 2014). This data is of great interest since it suggests that the chronic activation of D3 receptors produced by daily D3-preferential DA agonist does not have the same effects of l-DOPA. Accordingly, chronic stimulation with l-DOPA leads to hectopic over-expression of D3 receptor in medium spiny neurons of the striatum, a feature that was implicated in the pathophysiology of l-DOPA induced dyskinesia (LID) (Visanji et al., 2009); interestingly, these authors showed that chronic treatment with the selective D3 antagonists S33084 improve dyskinesia in a LID monkey experimental model.

Based on the hypothesis of dopaminergic hypofunction in mood disorders (reviewed in Liggio et al. 2013) and indirectly supported by its role on structural plasticity on dopaminergic neurons outlined by Collo et al. (2008), DA agonists have been used as add-on antidepressant treatment in several trials conducted the mid-2000 (e.g., Zarate et al., 2004; Aiken, 2007). However, with some exception, most of the trials were small open label studies with no placebo treatment; this fact has been limiting the possibility to draw final conclusions about the effective antidepressant role of DA agonist, in particular of pramipexole. Indirect support recently came from a large placebo controlled study in subjects with concurrent diagnosis of Parkinson Disease and depressive symptoms: significant antidepressant effects were reported directly associated to pramipexole (Barone et al., 2010). In addition, some recent reports indicate a satisfactory use in psychiatric practice (for example, Tran. et al. (2014)). (Figure 1).

4.4. Role of D3 receptor on impulse controlrelated adverse events Treatments with D3-preferential D2/D3 antagonists are associated to the occurrence of pathologic behaviour such as hypersexuality, pathologic gambling, excessive shopping and other compulsive dysfunctions (Weiss and Marsh, 2012). In a recent review performed on more that 2.7 million serious adverse events collected in the FDA database from 2003 to 2012, 1580 events were identified indicating impulse control disorders from the United States and 21 other countries: 710 were for D3-preferential D2/D3 agonists and 870 for other drugs. For the D3-preferential DA agonists the association was strongest for pramipexole (n = 410; Po.001) and ropinirole (n= 188; Po.001). A signal was also seen for aripiprazole, an antipsychotic classified as a partial agonist of the D3 receptor (n = 37; Po.001) (Moore et al., 2014). These data complement previous observations (Weiss and Marsh, 2012) and provide support the suggestion that D3-preferential D2/D3 agonists are associated with impulse control disorders and require a careful assessment of patient predisposing factor before advice for the treatment (Connelly and Lang 2014). However, a recent imaging study visualising D3 receptors in PD patients with or without impulse control disorders showed no difference in D3 receptor density (Payer et al., 2015), suggesting that a functional hyper-responsivity (that does not require an increased density of receptors) could be implicated.

5. 4.2.

Mood disorders

Conclusions

Restless leg syndrome

Among other indications, restless leg syndrome was successfully addressed by low doses of D3-preferential D2/D3 agonists pramipexole and ropinirole reducing the urge to

This review indicates that targeting D3 receptors with selective agents could provide beneficial effects in various human disorders. Important advances in the understanding of D3 receptors were obtained with the implementation of

Please cite this article as: Pich, E.M., Collo, G., Pharmacological targeting of dopamine D3 receptors: Possible clinical applications of selective agents. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2015.07.012

8

E.M. Pich, G. Collo

Figure 1 (A) Schematic representation of relevant intracellular pathways of D3 receptor-dependent structural plasticity in dopaminergic neurons. Abbreviations: MEK, Mitogen-activated protein kinase; ERK1/2, extracellular signal-regulated kinase; D3, dopamine D3 receptor; Giβγ, G protein; PI3K, phosphatidylinositol 3-kinase; Akt, serine threonine kinase (protein kinase B); mTORC1, mammalian target of rapamycin complex 1; p70S6K, p70 ribosomal S6 protein kinase; PD98059, MEK inhibitor; LY294002, PI3K inhibitor; rapamycin, mTORC1 inhibitor, (B) representative photomicrographs of primary cultures of Tyrosine Hydroxylase immunoreactive-positive dopaminergic neurons 72 h after exposure to vehicle or 10 μM ropinirole. The images show increased number and dendritic arborisation of dopaminergic neurons. Scale bar: 60 μm.

molecular neuroimaging, in particular using [(11)C](+ )-PHNO as ligand, by extensive testing of D3 receptor genetic polymorphisms, and with the exploration of large clinical database regarding efficacy and adverse events of D3-preferential D2/D3 agonists. Recent findings showed that, to some extent at variance of animal data, humans D3 receptors are expressed abundantly in SN/VTA, hypothalamus and pallidum and their activation/inhibition may produce different circuit engagement. We also learnt that prolonged treatments with D3-prefered D2/D3 agonist in patients with PD may reduce liability to progress into diskynesia later on and the peace of disease progression, effects possibly mediated by the restorative action of D3 receptors expressed in dopaminergic neurons via activation of specific intracellular pathways related to cell growth. Liabilities for D3-prefered D2/D3 agonist regarding impulse control disorders in predisposed individuals were further confirmed, their critical involvement in driving motivation and compulsive behavior being in line with the expected anti-addictive therapeutic potential of selective D3 antagonists or partial agonists observed preclinically. At the moment only few selective D3 antagonists or partial agonists are progressing in clinical development, the main area of applications being addiction and schizophrenia. An immediate opportunity for testing the hypothesis of a role of D3 receptors in these disorders is offered by the repurposing of bupropione for addiction and the progression of cariprazine (if used at low doses) in schizophrenia. Finally, there is expectation on the progression of the development of selective D3 antagonist ABT-925 currently positioned in schizophrenia, the only successful novel compound in this challenging area for drug discovery. In the near future it is expected that other compounds will

join ABT-925 so to provide a more robust body of evidence to support therapeutic applications in critical areas of unmet needs, in particular psychoses, cognitive disorders and addiction, for this new class of drugs.

Role of funding source EMP is full employee of Takeda Development Centre Europe, London. The funding source had no role since there is no actibe D3 receptor-related project present in the company. GC conducted this review as recipient of the grant ex 60%, University of Brescia.

Conflict of interest EMP is full employee of Takeda Development Centre Europe, London. GC is recipient of the grant ex 60%, University of Brescia and a grant from MIUR (PRIN 2009). In 2014–2015 GC signed a contract for a 6-month scientific project not related to D3 receptor with UCB, Bruxelles.

Acknowledgement EMP is full employee of Takeda Development Centre Europe. GC is recipient of the grant ex 60%, University of Brescia and a grant from MIUR (PRIN 2009).

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Please cite this article as: Pich, E.M., Collo, G., Pharmacological targeting of dopamine D3 receptors: Possible clinical applications of selective agents. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2015.07.012