WO2018219847A1 - Co-activators of mop and nop receptors in the treatment of addiction to drugs and/or psychostimulants - Google Patents

Co-activators of mop and nop receptors in the treatment of addiction to drugs and/or psychostimulants Download PDF

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WO2018219847A1
WO2018219847A1 PCT/EP2018/063884 EP2018063884W WO2018219847A1 WO 2018219847 A1 WO2018219847 A1 WO 2018219847A1 EP 2018063884 W EP2018063884 W EP 2018063884W WO 2018219847 A1 WO2018219847 A1 WO 2018219847A1
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cocaine
nop
treatment
ethano
cyclopropylmethyl
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Roberto Ciccocioppo
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Universita' Degli Studi Di Camerino
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence

Definitions

  • the present invention refers to the pharmaceutical field since it relates to co-activators of MOP and NOP receptors in the treatment of addiction to drugs and/or psychostimulants.
  • Cocaine is a widely abused illicit drug with a worldwide prevalence of 0.4 %, accounting for 14 to 20 million of individuals who used cocaine in their lifetime (Crime UNOoDa (2015) . World Drug Report 2015. United Nations publication (Sales No. E.15. XI.6) .
  • Cocaine addiction causes physical , psychiatric, socio-economic and judicial problems (Karila L, Gorelick D, Weinstein A, Noble F, Benyamina A, Coscas S, et al (2008) . New treatments for cocaine dependence : a focused review. The International Journal of Neuropsychopharmacology 11(03) : 425-438) , representing therefore a major social burden for which approved medications are still missing.
  • the fourth member of the opioid receptor superfamily-NOP receptor is considered a target for medication of cocaine addiction due to its anti-rewarding properties and limited side effects (tutfy K, Zaveri NT (2016) The Nociceptin Receptor as an Emerging Molecular Target for Cocaine Addiction , Progress in molecular biology and translational science 137: 149-181.; Toll L, (2013) , The Use of Bifunctional NOP/Mu and NOP Receptor Selective Compounds for the Treatment of Pain, Drug Abuse, and Psychiatric Disorders . Curr Pharm Design 19(42) : 7451-7460; averi NT (2011) .
  • Nociceptin/Orphanin FQ Receptor (NOP) as a Target for Drug Abuse Medications . Curr Top Med Chem 11(9) : 1151-1156) .
  • Nociceptin is the endogenous ligand of NOP that was proved to inhibit cocaine-induced conditioned place preference (CPP) in the rat (Kotlinska J, Wichmann J, Legowska A, Rolka K, Silberring J (2002) .
  • Orphanin FQ/'nociceptin but not Ro 65-6570 inhibits the expression of cocaine-induced conditioned place preference.
  • nociceptin failed to induce either place preference or aversion even at a dose as high as 1000 ng/rat (Lambert DG, Bird MF, Rowbotham DJ (2015b) .
  • Cebranopadol a first in-class example of a nociceptin/orphanin FQ receptor and opioid receptor agonist.
  • British journal of anaesthesia 114 (3) : 364-366) .
  • NOP agonists are devoid of abuse liability (Lin AP, Ko M-C (2012) . The therapeutic potential of nociceptin/orphanin FQ receptor agonists as analgesics without abuse liability.
  • ACS chemical neuroscience 4(2) : 214-224) The therapeutic potential of nociceptin/orphanin FQ receptor agonists as analgesics without abuse liability.
  • Cebranopadol is a compound already tested in both completed and ongoing phase II and III clinical trials for pain treatment (Lambert DG, Bird MF, Rowbotham DJ (2015b) .
  • Cebranopadol a first in-class example of a nociceptin/orphanin FQ receptor and opioid receptor agonist.
  • Buprenorphine is a long-acting partial agonist at MOP and antagonist at DOP and KOP receptors, and together with methadone represent a first line treatment for heroin addiction (Kakko J, Gronbladh L, Svanborg KD, von Wachenfeldt J, Ruck C, Rawlings B, Nilsson LH, yoga M (2007) A stepped care strategy using buprenorphine and methadone versus conventional methadone maintenance in heroin dependence : a randomized controlled trial.
  • Neuropsychopharmacology official publication of the /American College of Neuropsychopharmacology 7:157-162; Strain EC, Stitzer ML, Liebson IA, Bigelow GE (1994) Buprenorphine versus methadone in the treatment of opioid- dependent cocaine users.
  • Psychopharmacology 116: 401-406) Inconsistent results were also obtained in clinical trials in opiate-dependent subjects co-abusing cocaine, where in some cases buprenorphine treatment was associated also with a reduction in cocaine use (Kosten TR, Kleber HD, Morgan C (1989b) Treatment of cocaine abuse with buprenorphine.
  • buprenorphine has a high ligand affinity for these receptors and its effect on cocaine is not blocked but rather enhanced by naltrexone.
  • Addiction biology 19 575-586; Mello NK, Lukas SE, Mendelson JH, Drieze J (1993) Naltrexone-buprenorphine interactions : effects on cocaine self-administration .
  • Science translational medicine 4 : 146rall0.
  • buprenorphine In addition to its activity at classical MOP, DOP and KOP receptors, buprenorphine also acts as an agonist/partial agonist at the nociceptin/orphanin FQ peptide (NOP) receptor (Bloms-Funke P, Gillen C, Schuettler AJ, Wnendt S (2000) Agonistic effects of the opioid buprenorphine on the nociceptin/OFQ receptor. Peptides 21:1141-1146; Huang P, Kehner GB, Cowan A, Liu-Chen LY (2001) Comparison of pharmacological activities of buprenorphine and norbuprenorphine : norbuprenorphine is a potent opioid agonist.
  • NOP nociceptin/orphanin FQ peptide
  • N/OFQ endogenous ligand nociception/orphanin FQ
  • Orphanin FQ/noclceptln blocks methamphetamine place preference in rats.
  • Psychopharmacology 154:1- 7) .
  • NOP receptor KO mice activation of NOP receptors by N/OFQ resulted in blockade of cocaine sensitization, an effect that was absent in NOP receptor KO mice (Bebawy D, Marquez P, Samboul S, Parikh D, Hamid A, Lutfy K (2010) Orphanin FQ/nociceptin not only blocks but also reverses behavioral adaptive changes induced by repeated cocaine in mice.
  • mice lacking the NOP receptor show greater conditioned place preference for cocaine compared to wild type littermates (Marquez P, Nguyen AT, Hamid A, Lutfy K (2008) The endogenous OFQ/N/ORL-1 receptor system regulates the rewarding effects of acute cocaine . Neuropharmacology 54:564-568) .
  • buprenorphine as potential cocaine addiction treatment is owed to its too low affinity to NOP compared with MOP (about 50 times lower) (Khroyan TV, Polgar WE, Cami-Kobeci G, Husbands SM, Zaveri NT, Toll L (2011a) .
  • WO2016/116280 discloses cebranopadol for the treatment or the prevention of pain and/or opioid drug dependence in a subject with impaired hepatic and/or renal function.
  • US2012034297 discloses cebranopadol for the treatment of pain.
  • WO2016124513 discloses cebranopadol being analgesic.
  • US5075341 discloses buprenorphine for the treatment of cocaine abuse .
  • EP0432945 discloses transdermal delivery system for the treatment of cocaine or heroin addiction including buprenorphine.
  • the inventors of the present invention in view of the findings of the prior art, investigated the involvement of NOP and MOP receptors in the cellular mechanism underlying addiction, abuse, dependence, craving, relapse to drugs and psychostimulants, in order to clarify the mechanism of action and identify new molecules useful in vanquishing drug addiction .
  • the same inventors investigated compounds with high affinities and strong potency to both NOP and MOP, which may have promising potential for medication of addiction, abuse, dependence, craving, relapse to drugs and psychostimulants with none, or limited, side effects.
  • the same inventors clarified the role of NOP and MOP in the action of buprenorphine, which was already known for the treatment of cocaine addiction, by investigating the effect of buprenorphine on cocaine self-administration after pretreatment with the classical opioid receptor antagonist naltrexone in the presence of selective NOP antagonists, then tested small-molecule NOP agonist/MOP partial agonists and selective NOP agonist and their effect on sucrose self- administration .
  • cebranopadol abolishes cocaine consumption by selectively and simultaneously targeting NOP and MOP receptors.
  • At least one NOP/MOP receptors selective agonist molecule selected from the group consisting of: compound of general formula (I)
  • x is halogen, H
  • R is CH 3 , CH 2 CH(CH 2 ) 2 , C (CH 3 ) 3 , C (CH 3 ) 2 C 2 H 5 , CH 2 C(CH 3 ) CH 2 C ( CH 3 ) 2 CeH 5 , p-C ( CH 3 ) 3 CeH 4 , and cebranopadol with the proviso that the molecule of formula (I) is not (2S) -2- [ (5R, 6R, 7R, 14S) -17- cyclopropylmethyl-4 , 5-epoxy-6, 14-ethano-3-hydroxy-6- methoxymorphinan-7-yl] -3, 3-dimethylbutan-2-ol and 2S) -2-
  • Another object of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmacologically effective amount of at least one NOP/MOP receptors selective agonist molecule selected from the group consisting of: compound of general formula (I)
  • R is CH 3 , CH 2 CH(CH 2 ) 2 , C (CH 3 ) 3 , C (CH 3 ) 2 C 2 H 5 , CH 2 C(CH 3 ) 3 , CH 2 C ( CH 3 ) 2 CeH 5 , p-C ( CH 3 ) 3 CeH 4 , and cebranopadol with the proviso that molecule of formula (I) is not (2S)-2- [ (5R, 6R, 7R, 14S) -17-cyclopropylmethyl-4 , 5-epoxy-6, 14-ethano-3- hydroxy-6-methoxymorphinan-7-yl] -3, 3-dimethylbutan-2-ol and 2S) -2- (5R, 6R, 7R, 14S) -N-cyclopropylmethyl-4 , 5-epoxy-6 , 14- ethano-3-hydro xy-6-methoxymorphinan-7-yl -3 , 3-dimethylpentan- 2-ol, and
  • Figure 1 shows the effect of cebranopadol on cocaine (A) and saccharin (B) self-administration. Values are presented as mean ⁇ SEM. Statistical differences: *p ⁇ 0.05 and ***p ⁇ 0.001 vs vehicle; #p ⁇ 0.05 and ##p ⁇ 0.01 vs 25 g/kg.
  • Figure 2 shows the effect of cebranopadol on motivation for cocaine expressed as breakpoint reached in SA session under a progressive ratio schedule of reforcement, data are presented as mean ⁇ SEM. Statistical differences: *p ⁇ 0.05 vs vehicle; #p ⁇ 0.05 vs 25 g/kg.
  • Figure 3 shows the pharmacological mechanism by which cebranopadol decreases cocaine self-administration, for each compound administration of vehicle is indicated by the "-" mark while administration of the active agent is indicated by the "+” mark, data are presented as mean ⁇ SEM.
  • Figure 4 shows chronic cebranopadol treatment on cocaine self- administration. Data are presented as mean ⁇ SEM and show the last two days pre-treatment, seven days of treatment and two days post-treatment, statistical differences: *p ⁇ 0.05, **p ⁇ 0.01, and ****p ⁇ 0.0001 vs the last day pre-treatment.
  • Figure 5 shows the effect of cebranopadol on place conditioning test, data are presented as mean ⁇ SEM. *p ⁇ 0.05 vs control group.
  • Figure 6 shows the effect of cebranopadol on intravenous self- administration of different concentrations of heroin.
  • Figure 7 shows the results of a break point measure under progressive ratio schedule of reinforcement following administration of different doses of cebranopadol in rats self-administering heroin.
  • Figure 8 shows the results of Heroin-associated cues reinstated heroin seeking respect to extinction with cebranopadol .
  • Figure 9 shows the results of the effect of cebranopadol on stress induced reinstatement with yohimbine.
  • addiction and/or abuse and/or dependence to drugs and/or psychostimulants means a psychological desire to use drugs and/or psychostimulants regularly which leads to dependency and addiction.
  • MOP receptor means mu-opioid (MOP) receptor.
  • NOP receptor means nociceptin receptor, also known as the nociceptin/orphanin FQ (N/OFQ) receptor or OPRL-1 receptor or kappa-type 3 opioid receptor.
  • agonist molecule means a chemical compound binding a receptor and activating the receptor to produce a biological response.
  • buprenorphine means (2S) -2- [ (5R, 6R, 7R, 14S) -17-cyclopropylmethyl-4, 5-epoxy- 6, 14-ethano-3-hydroxy-6-methoxymorphinan-7-yl] -3, 3- dimethylbutan-2-ol .
  • 2S)-2- (5R, 6R, 7R, 14S) -N-cyclopropylmethyl-4, 5-epoxy-6, 14-ethano-3- hydroxy-6-methoxymorphinan-7-yl -3, 3-dimethylpentan-2-ol is also named as BU08028.
  • a pharmacologically effective amount means the dosage of the active ingredient producing a therapeutic response or desired effect without side effects.
  • pharmaceutically acceptable excipients means any chemical alongside the active ingredient of a medication, such as, and not limited to, long- term stabilization agents, bulking agents, fillers, diluents, agents facilitating drug absorption, agents reducing viscosity, agents enhancing solubility, agents facilitating powder flowability or non-stick properties, agents aiding in vitro stability, agents preventing denaturation or aggregation, agents improving shelf life, depending also upon the route of administration and the dosage form, which can be selected by the person skilled in the art in view of his common general knowledge.
  • long- term stabilization agents such as, and not limited to, long- term stabilization agents, bulking agents, fillers, diluents, agents facilitating drug absorption, agents reducing viscosity, agents enhancing solubility, agents facilitating powder flowability or non-stick properties, agents aiding in vitro stability, agents preventing denaturation or aggregation, agents improving shelf life, depending also upon the route of administration and the dosage form, which can be selected by the person skilled
  • drug means opioids, sedatives, hypnotics, anxiolytics, including benzodiazepines and barbiturates, cocaine, amphetamine, amphetamine-like, hallucinogens, cathinones, inhalant, polysubstance , phencyclidines , phencyclidine-like , nicotine.
  • psychostimulant means for example amphetamines, substituted amphetamines, cocaine analogues, caffeine, methamphetamines , 3,4- Methylenedioxymethamphetamine, Methylenedioxypyrovalerone,
  • Mephedrone nicotine, Propylhexedrine, Pseudoephedrine , Catha edulis (Khat) .
  • Object of the present invention is at least one NOP/MOP receptors selective agonist molecule selected from the group consisting of: compound of general formula (I)
  • R is CH 3 , CH 2 CH(CH 2 ) 2 , C (CH 3 ) 3 , C (CH 3 ) 2 C 2 H 5 , CH 2 C(CH 3 ) CH 2 C ( CH 3 ) 2 CeH 5 , p-C ( CH 3 ) 3 CeH 4 , and cebranopadol with the proviso that the molecule of formula (I) is not (2S) -2- [ (5R, 6R, 7R, 14S) -17-cyclopropylmethyl-4 , 5-epoxy 6, 14-ethano-3-hydroxy-6-methoxymorphinan-7-yl] -3, 3- dimethylbutan-2-ol and 2S) -2- (5R, 6R, 7R, 14S) -N cyclopropylmethyl-4 , 5-epoxy-6, 14-ethano-3-hydro xy-6 methoxymorphinan-7-yl -3, 3-dimethylpentan-2-ol, for use for the treatment of addiction and/
  • Another object of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmacologically effective amount of at least one NOP/MOP receptors selective agonist molecule selected from the group consisting of: compound of general formula (I)
  • R is CH 3 , CH 2 CH(CH 2 ) 2 , C (CH 3 ) 3 , C (CH 3 ) 2 C 2 H 5 , CH 2 C(CH 3 ) 3 , CH 2 C ( CH 3 ) 2 CeH 5 , p-C ( CH 3 ) 3 CeH 4 , and cebranopadol with the proviso that the molecule of formula (I) is not (2S) -
  • compound of formula (I) is selected from the group consisting of:
  • NOP/MOP receptors selective agonist molecules are selected from the group consisting of: cebranopadol and (20R, 5a, 6R, 7R, 14a) -20- ( 17-Cyclopropylmethyl-7 , 8-dihydro-4, 5- epoxy-6, 14-ethano-3-hydroxy-6-methoxy-morphinan-7-yl) -40, 40- dimethylpentan-2 O-ol or mixture thereof.
  • drugs and/or psychostimulants is selected from the group consisting of: opioids, sedatives, hypnotics, anxiolytics, including benzodiazepines and barbiturates, cocaine, amphetamine, amphetamine-like, hallucinogens, cathinones, inhalant, polysubstance, phencyclidines , phencyclidine-like , nicotine, substituted amphetamines, cocaine analogues, caffeine, methamphetamines , 3,4- Methylenedioxymethamphetamine, Methylenedioxypyrovalerone, Mephedrone , Propylhexedrine, Pseudoephedrine, Catha edulis (Khat) .
  • opioids sedatives, hypnotics, anxiolytics, including benzodiazepines and barbiturates
  • cocaine amphetamine
  • amphetamine-like hallucinogens
  • cathinones cathinone
  • More preferably drug is selected from the group consisting of: heroin, cocaine.
  • cebranopadol for use for the treatment of addiction and/or abuse and/or dependence and/or craving and/or relapse to cocaine .
  • the invention refers also to a method of treating drug addiction and/or drug abuse and/or drug dependence, preferably drug being cocaine and/or psychostimulants, dependence by administering a pharmaceutically effective dose of a NOP/MOP receptors selective agonist molecule as previously defined to a patient in need thereof.
  • NOP/MOP receptor agonist To shed light on The mechanism of action of NOP/MOP receptor agonist an extensive pharmacological investigation using a classical opioid receptor antagonist, NOP receptor antagonists and their combination, as well as new compounds mimicking some but not all pharmacological properties of buprenorphine was conducted .
  • Cocaine hydrochloride was dissolved in sterile physiological saline at a concentration of .25mg/0.1 ml and given intravenously (Knoll et al . ) .
  • Naltrexone was dissolved in distilled water and was administered intraperitoneally (IP) at the doses of 0.25, 1.0, 2.5 and 5.0mg/kg/ml 60min prior the test phase.
  • Buprenorphine hydrochloride was administered IP at the doses of 0.3, 1.0 and 3.0mg/kg/ml 90min prior the test phase.
  • SB-612111 was administered per os via gavage in 10.0 and 30.0mg/kg/ml 60min prior test phase.
  • AT-034 (AT-034), (AT-201) and (AT-202) (NOP/MOP agonist compounds), were synthesized by Dr. Zaveri (Astraea Therapeutics, USA) . They were administered subcutaneously (Knoll et al . ) 60 minutes prior to the test phase.
  • the self-administration stations consisted of operant conditioning chambers (Med Associate Inc.) enclosed in sound attenuating, ventilated environmental cubicles. Each chamber was equipped with two retractable levers located in the front panel of the chamber. A plastic tube that was connected to the catheter before the beginning of the session delivered cocaine. An infusion pump was activated by responses on the right (active) lever, while responses on the left (inactive) lever were recorded but did not result in any programmed consequences. Activation of the pump resulted in a delivery of 0.1 ml of fluid. An IBM compatible computer controlled the delivery of cocaine solution and recording of the behavioral data.
  • FR1 Fixed Ratio
  • FR5 Fixed Ratio
  • naltrexone did not block the effect of buprenorphine on cocaine self-administration.
  • naltrexone (0.25, 1 and 2.5mg/kg), SB-612111 (10 and 30mg/kg) and their combination against buprenorphine was tested.
  • the experiment was carried out in a within subject Latin square counterbalance design.
  • mice Male Wistar rats (Charier River, Italy) , weighing 270-320 g at the beginning of the experiments were used. Pairs of rats were housed in a room with artificial 12/12 h light/dark cycle (lights off at 8 am) , at constant temperature (20-22°C) and humidity (45-55%) . Food (4RF18, Mucedola, Settimo Milanese, Italy) and water were provided ad libitum except during session time. All the experiments were conducted during the dark phase of the light/dark cycle. Rats were allowed to acclimate to the housing room for one week and were handled 3 times before any experimental manipulation. All the procedures were carried out in accordance with the European Community Council directive and the National Institutes of Health guidelines for the care and use of laboratory animals.
  • Cocaine hydrochloride and morphine hydrochloride were dissolved in sterile saline. Saccharin (Sigma, Italy) was dissolved in tap water. Cebranopadol (Biochempartner Co., Ltd, China) for operant tests was dissolved with 5% DMSO and 95% glucose (5%) . Cebranopadol for place conditioning was dissolved in 10% DMSO + 5% Cremophor EL + 85% saline.
  • the selective NOP antagonist SB-612111 was kindly provided by Eli Lilly (USA) ; it was dissolved in 1 M H3P04 in distilled water (1:1) . MOPr antagonist naltrexone (Sigma, USA) was dissolved in distilled water.
  • SA stations consisted of operant conditioning chambers (Med Associate Inc.) enclosed in sound attenuating, ventilated environmental cubicles. Each chamber was equipped with two retractable levers located in the front panel of the chamber. A plastic tube that was connected to the catheter before the beginning of the session delivered cocaine. An infusion pump was activated by responses on the right (active) lever, while responses on the left (inactive) lever were recorded but did not result in any programmed consequences. Activation of the pump resulted in a delivery of 0.1 ml of fluid. An IBM compatible computer controlled the delivery of cocaine solution and recording of the behavioral data .
  • Rats (n 16) were initially trained to a 2-h daily cocaine SA sessions under Fixed Ratio 1 (FR1) schedule of reinforcement for 10 days, then reinforcement schedule was increased to FR5 until stable baseline of responding (less 10% variation for 3 consecutive days) was reached. Following each cocaine infusion (0.25 mg/ 0. lml intra-venous ) , a 20 sec Time Out (TO) period was presented during which responses at the active lever had no programmed consequences. Cebranopadol (0, 25, 50 g/kg per os (p.o.) lh before test) was tested in a Latin square counterbalanced design. At least 3 days interval during which cocaine self-administration baseline was re-established was allowed between drug tests.
  • FR1 Fixed Ratio 1
  • Preference score was defined as the time spent in the drug-paired compartment minus the time spent in the vehicle-paired compartment. For the control group, as they received vehicle in both compartments and they did not show preference for either of the compartments, preference score was computed subtracting the time spent in compartment A to the time spent in compartment B for half of the rats and vice versa for the other half.
  • Cebranopadol place conditioning by oneway ANOVA with groups as independent factors (cebranopadol: 0, 10 and 50 g/kg) . Results were expressed as mean ⁇ SEM and statistical significance was set as: p ⁇ 0.05.
  • cebranopadol significantly reduced cocaine self-administration under fixed and progressive ratio schedule of reinforcements indicating reduced motivation for cocaine following drug treatment.
  • the effect was substance-specific because when ceranopadol was tested on saccharin self-administration, at the lowest dose it slightly increased the intake and at highest one it left the intake unchanged.
  • the tendency of cebranopadol to increase the consumption of sweet solutions is consistent with its ability to activate MOP receptors.
  • the inhibitory effect of cebranopadol on cocaine self-administration was increased during chronic treatment, suggesting that following repeated drug administrations this effect is not subjected to development of tolerance.
  • cebranopadol The inhibitory effect of cebranopadol on cocaine self-administration is blocked by coadministration of SB-612111 and naltrexone, which indicates that co-activation of MOP and NOP is an essential step mediating this drug action.
  • Cebranopadol does not elicit place preference.
  • Cebranopadol is a high affinity agonist at both MOP and NOP receptors and is almost equipotent in activating both receptors.
  • FR1 Fixed Ratio 1
  • the first phases was the discrimination training.
  • the purpose of this phase was to train rats to self-administer heroin while simultaneously establishing discriminative stimuli associated with heroin availability vs non-availability.
  • Once stable heroin SA baseline was established as describe for experiment-1 (heroin dose 20 g/infusion) , rats were subjected to discrimination learning as follow.
  • either heroin or saline was available as the only infusion solution.
  • Each day include one saline and two heroin sessions conducted in random order. Sessions were initiated by the extension of the lever and presentation of the respective discriminative stimulus, which remained on for the entire duration of the session.
  • Discriminative stimulus associated with heroin availability was an intermittent beep tone while that associated with saline was the continuous illumination of the self-administration chamber by the house light. Both heroin and saline infusions were followed by 20s timeout. Timeout was signalled by illumination of the cue-light for heroin and by a white noise for saline. Discrimination training regime was maintained for 20 days. Before every saline session, catheters were flushed with heparinized solution to prevent the heroin left-over in the dead volume of the catheter to reinforce the first infusion of the saline session .
  • the second phase was the extinction training, following the discrimination, and consisting of 1 hour daily session during which active lever pressing activated the syringe pump motor but no fluid was delivered, and discriminative and discrete stimuli were not presented.
  • the third phase was the cue-induced reinstatement and Cebranopadol treatment, wherein the reinstatement tests began the day after the last extinction session. This test lasted lh under conditions identical to those during the discrimination phase, except that heroin and saline were not made available. Rats were tested under the saline-paired condition on day one and from day two they were tested for cue-induced reinstatement of heroin seeking by re-exposure to heroin- paired stimuli. One hour before cue-induced reinstatement of heroin seeking tests rats were treated with cebranopadol (0, 25, 50 g/kg) doses administered in counterbalanced order. Cebranopadol was administered by gavage . Responses at both active and inactive levers were recorded. Between tests rats remained in their home-cages .
  • the effect of cebranopadol on yohimbine-induced heroin relapse was investigated in 11 rats and it consisted of three phases.
  • the first phase was the self-administration training, wherein the rats were trained to 2-h daily heroin SA as described before.
  • the second phase was the extinction training wherein, after training, rats entered the extinction phase where they run 1 hour daily for 10 days. During extinction, active lever pressing activated the syringe pump motor but did not result in fluid delivery.
  • the third phase was yohimbine-induced reinstatement of heroin seeking.
  • Yohimbine-induced reinstatement session was similar to a standard extinction session, except that 1 hour prior to test rats were orally administered with cebranopadol (0, 25, 50 g/kg) and 30min later they received an intraperitoneal injection of yohimbine ( 1.25mg/kg/ml ) . Tests were repeated every fourth day and cebranopadol doses were administered in counterbalanced order. Between tests rats performed standard extinction training between sessions. Rats rapidly acquired heroin SA and maintained stable responding at the different doses (7, 20, 60 ]ig , as shown in figure 6.
  • Newman-Keuls as post-hoc analysis revealed that re-exposure to heroin-predictive cues reinstated heroin seeking and the dose of 50 g/kg of cebranopadol reduced cue-induced heroin seeking. Both cue and cebranopadol effect were specific for active lever as inactive was always very low and not affected by experimental conditions, as shown in figure 8.
  • cebranopadol is efficacious not only in treating withdrawal in opioids dependent subjects but is also attenuates opioid consumption and reduces the risks of relapse in abstinent previously heroin users.

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Abstract

NOP/MOP receptors selective agonist molecules for the treatment of addiction, abuse, dependence,craving, relapse to drugs and/or psychostimulants are disclosed.

Description

Co-activators of MOP and NOP receptors in the treatment of addiction to drugs and/or psychostimulants
*****
Background of the invention The present invention refers to the pharmaceutical field since it relates to co-activators of MOP and NOP receptors in the treatment of addiction to drugs and/or psychostimulants.
State of the art
Cocaine is a widely abused illicit drug with a worldwide prevalence of 0.4 %, accounting for 14 to 20 million of individuals who used cocaine in their lifetime (Crime UNOoDa (2015) . World Drug Report 2015. United Nations publication (Sales No. E.15. XI.6) . Cocaine addiction causes physical , psychiatric, socio-economic and judicial problems (Karila L, Gorelick D, Weinstein A, Noble F, Benyamina A, Coscas S, et al (2008) . New treatments for cocaine dependence : a focused review. The International Journal of Neuropsychopharmacology 11(03) : 425-438) , representing therefore a major social burden for which approved medications are still missing.
The fourth member of the opioid receptor superfamily-NOP receptor is considered a target for medication of cocaine addiction due to its anti-rewarding properties and limited side effects (tutfy K, Zaveri NT (2016) The Nociceptin Receptor as an Emerging Molecular Target for Cocaine Addiction , Progress in molecular biology and translational science 137: 149-181.; Toll L, (2013) , The Use of Bifunctional NOP/Mu and NOP Receptor Selective Compounds for the Treatment of Pain, Drug Abuse, and Psychiatric Disorders . Curr Pharm Design 19(42) : 7451-7460; averi NT (2011) . The Nociceptin/Orphanin FQ Receptor (NOP) as a Target for Drug Abuse Medications . Curr Top Med Chem 11(9) : 1151-1156) . Nociceptin is the endogenous ligand of NOP that was proved to inhibit cocaine-induced conditioned place preference (CPP) in the rat (Kotlinska J, Wichmann J, Legowska A, Rolka K, Silberring J (2002) . Orphanin FQ/'nociceptin but not Ro 65-6570 inhibits the expression of cocaine-induced conditioned place preference. Behavioural Pharmacology 13(3) : 229-235) and NOP knockout (KO) mice showed higher cocaine-induced CPP than their wild type counterpart (Marquez P, Nguyen AT, Hamid A, Lutfy K (2008) . The endogenous OFQ/N/ORL-1 receptor system regulates the rewarding effects of acute cocaine . Neuropharmacology 54 (3) : 564-568).
Nociceptin abolished cocaine-elicited psychomotor sensitization in wild type but not in NOP KO mice (Bebawy D, Marquez P, Samboul S, Parikh D, Hamid A, Lutfy K (2010) . Orphanin FQ/nociceptin not only blocks but also reverses behavioral adaptive changes induced by repeated cocaine in mice. Biological psychiatry 68(3) : 223-230) .
Noteworthy, intra-cerebro-ventricular injection of nociceptin failed to induce either place preference or aversion even at a dose as high as 1000 ng/rat (Lambert DG, Bird MF, Rowbotham DJ (2015b) . Cebranopadol : a first in-class example of a nociceptin/orphanin FQ receptor and opioid receptor agonist. British journal of anaesthesia 114 (3) : 364-366) . Consistently, NOP agonists are devoid of abuse liability (Lin AP, Ko M-C (2012) . The therapeutic potential of nociceptin/orphanin FQ receptor agonists as analgesics without abuse liability. ACS chemical neuroscience 4(2) : 214-224) .
Cebranopadol is a compound already tested in both completed and ongoing phase II and III clinical trials for pain treatment (Lambert DG, Bird MF, Rowbotham DJ (2015b) . Cebranopadol: a first in-class example of a nociceptin/orphanin FQ receptor and opioid receptor agonist. British journal of anaesthesia 114(3): 364-366; Schunk S, Linz K, Hinze C, Frormann S, Oberboersch S, Sundermann B, et al (2014). Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol. ACS medicinal chemistry letters 5(8): 857-862) with an almost full agonist activity for both NOP and MOP, as radioligand binding data revealed sub-nanomolar affinity to both rat and human NOP and MOP 20 times higher than DOP and KOP receptors (Linz K, Christoph T, Tzschentke TM, Koch T, Schiene K, Gautrois M, et al (2014) . Cebranopadol: A Novel Potent Analgesic Nociceptin/Orphanin FQ Peptide and Opioid Receptor Agonists . Journal of Pharmacology and Experimental Therapeutics 349(3): 535-548) . Buprenorphine is a long-acting partial agonist at MOP and antagonist at DOP and KOP receptors, and together with methadone represent a first line treatment for heroin addiction (Kakko J, Gronbladh L, Svanborg KD, von Wachenfeldt J, Ruck C, Rawlings B, Nilsson LH, Heilig M (2007) A stepped care strategy using buprenorphine and methadone versus conventional methadone maintenance in heroin dependence : a randomized controlled trial. The American journal of psychiatry 164:797-803; Kleber HD (2003) Pharmacologic treatments for heroin and cocaine dependence . The American journal on addictions / American Academy of Psychiatrists in Alcoholism and Addictions 12 Suppl 2:S5-S18; Kosten TR (1990) Current pharmacotherapies for opioid dependence .
Psychopharmacology bulletin 26:69-74).
Studies in rats showed that buprenorphine attenuates the expression of cocaine sensitization and other cocaine-related behaviors by increasing basal levels of glutamate in the nucleus accumbens, which serve to decrease the effectiveness of cocaine or cocaine-associated cues (Placenza FM, Rajabi H, Stewart J (2008) Effects of chronic buprenorphine treatment on levels of nucleus accumbens glutamate and on the expression of cocaine-induced behavioral sensitization in rats.
Psychopharmacology 200:347-355) . Reduction of cocaine self- administration in rats following buprenorphine treatment was also reported (Sorge RE, Stewart J (2006a) The effects of chronic buprenorphine on intake of heroin and cocaine in rats and its effects on nucleus accumbens dopamine levels during self-administration . Psychopharmacology 188:28-41).
Clinical studies show mixed results, in some human laboratory studies, buprenorphine was able to reduce self-reported cocaine craving and cocaine self-administration (Kosten TR, Kleber ED, Morgan C (1989a) Role of opioid antagonists in treating intravenous cocaine abuse. Life sciences 44:887-892.; Montoya ID, Gorelick DA, Preston KL, Schroeder JR, Umbricht A, Cheskin LJ, Lange WR, Contoreggi C, Johnson RE, Fudala PJ (2004) Randomized trial of buprenorphine for treatment of concurrent opiate and cocaine dependence . Clinical pharmacology and therapeutics 75:34-48.; Schottenfeld RS, Pakes J, Ziedonis D, Kosten TR (1993) Buprenorphine : dose- related effects on cocaine and opioid use in cocaine-abusing opioid-dependent humans. Biological psychiatry 34:66-74) . In other studies these findings were not confirmed (Foltin RW, Fischman MW (1996) Effects of methadone or buprenorphine maintenance on the subjective and reinforcing effects of intravenous cocaine in humans. The Journal of pharmacology and experimental therapeutics 278:1153-1164.; Kouri EM, Lukas SE, Mendelson JH (1996) P300 assessment of opiate and cocaine users: effects of detoxification and buprenorphine treatment. Biological psychiatry 40:617-628; endelson JH, Teoh SK, Mello NK, Ellingboe J (1992) Buprenorphine attenuates the effects of cocaine on adrenocorticotropin (ACTH) secretion and mood states in man. Neuropsychopharmacology : official publication of the /American College of Neuropsychopharmacology 7:157-162; Strain EC, Stitzer ML, Liebson IA, Bigelow GE (1994) Buprenorphine versus methadone in the treatment of opioid- dependent cocaine users. Psychopharmacology 116: 401-406) . Inconsistent results were also obtained in clinical trials in opiate-dependent subjects co-abusing cocaine, where in some cases buprenorphine treatment was associated also with a reduction in cocaine use (Kosten TR, Kleber HD, Morgan C (1989b) Treatment of cocaine abuse with buprenorphine. Biological psychiatry 26:637-639) whereas other trials did not confirm this effect (Compton PA, Ling W, Charuvastra VC, Wesson DR (1995) Buprenorphine as a pharmacotherapy for cocaine abuse: a review of the evidence. Journal of addictive diseases 14:97-114; chottenfeld RS, Pakes JR, Oliveto A, Ziedonis D, Kosten TR (1997) Buprenorphine vs methadone maintenance treatment for concurrent opioid dependence and cocaine abuse. Archives of general psychiatry 54:713-720) .
A possible explanation for these variable effects of buprenorphine on cocaine consumption could be the different dose regimen used across the studies. In fact, in a more recent report in which a sublingual dosage form of buprenorphine was used, it was found that in heroin addicts that also abused cocaine, buprenorphine reduced consumption of both drugs. Intriguingly however, the effect on cocaine occurred only at very high doses and appeared to be independent from that on heroin (Montoya ID, Gorelick DA, Preston KL, Schroeder JR, Umbricht A, Cheskin LJ, Lange WR, Contoreggi C, Johnson RE, Fudala PJ (2004) Randomized trial of buprenorphine for treatment of concurrent opiate and cocaine dependence. Clinical pharmacology and therapeutics 75:34-48) .
This finding was replicated in another cohort of heroin addicted patients, in which buprenorphine was also given at high doses and it was also found that the combination of buprenorphine and the nonselective MOP, DOP and KOP antagonist naltrexone resulted in an even more pronounced effect (Gerra G, Fantoma A, Zaimovic A (2006) Naltrexone and buprenorphine combination in the treatment of opioid dependence. J Psychopharmacol 20:806-814) . Thus, buprenorphine has a high ligand affinity for these receptors and its effect on cocaine is not blocked but rather enhanced by naltrexone.
Further data showed that when buprenorphine was tested in combination with low doses of naltrexone to block its MOP partial agonist effects, the inhibitory effect on cocaine self-administration and cocaine-primed reinstatement was preserved (Cordery SF, Taverner A, Ridzwan IE, Guy RH, Delgado-Charro MB, Husbands SM, Bailey CP (2014) A non- rewarding, non-aversive buprenorphine/naltrexone combination attenuates drug-primed reinstatement to cocaine and morphine in rats in a conditioned place preference paradigm. Addiction biology 19 : 575-586; Mello NK, Lukas SE, Mendelson JH, Drieze J (1993) Naltrexone-buprenorphine interactions : effects on cocaine self-administration . Neuropsychopharmacology official publication of the American College of Neuropsychopharmacology 9:211-224; Wee S, Vendruscolo LF, Misra KK, Schlosburg JE, Koob GF (2012) A combination of buprenorphine and naltrexone blocks compulsive cocaine intake in rodents without producing dependence. Science translational medicine 4 : 146rall0. ; Witkin JM, Johnson RE, Jaffe JH, Goldberg SR, Grayson NA, Rice KC, Katz JL (1991) The partial opioid agonist , buprenorphine , protects against lethal effects of cocaine. Drug and alcohol dependence 27:177-184).
In addition to its activity at classical MOP, DOP and KOP receptors, buprenorphine also acts as an agonist/partial agonist at the nociceptin/orphanin FQ peptide (NOP) receptor (Bloms-Funke P, Gillen C, Schuettler AJ, Wnendt S (2000) Agonistic effects of the opioid buprenorphine on the nociceptin/OFQ receptor. Peptides 21:1141-1146; Huang P, Kehner GB, Cowan A, Liu-Chen LY (2001) Comparison of pharmacological activities of buprenorphine and norbuprenorphine : norbuprenorphine is a potent opioid agonist. The Journal of pharmacology and experimental therapeutics 297 : 688-695; Lutfy K, Eitan S, Bryant CD, Yang YC, Saliminejad N, Walwyn W, Kieffer BL, Takeshima H, Carroll El, Maidment NT, Evans CJ (2003) Buprenorphine-induced antinociception is mediated by mu-opioid receptors and compromised by concomitant activation of opioid receptor-like receptors . The Journal of neuroscience : the official journal of the Society for Neuroscience 23 : 10331-10337; Wnendt S, Kruger T, Janocha E, Hildebrandt D, Englberger W (1999) Agonistic effect of buprenorphine in a nociceptin/OFQ receptor-triggered reporter gene assay. Molecular pharmacology 56 : 334-338) , an effect that occurs only at high doses of the drug.
Consistent with this mechanism, in previous studies in alcohol preferring rats, the same inventors have shown that at high doses, buprenorphine reduced alcohol intake through activation of NOP receptors whereas at low doses it enhanced drinking by activating MOP receptors (Ciccocioppo R, Economidou D, Rimondini R, Sommer W, Massi M, Heilig M (2007) Buprenorphine reduces alcohol drinking through activation of the noclceptln/'orphanln FQ-NOP receptor system. Biological psychiatry 61:4-12).
Activation of the NOP receptor by the endogenous ligand nociception/orphanin FQ (N/OFQ) has been shown to reduce the expression of CPP engendered by either cocaine or methamphetamine (Kotllnska J, Wlchmann J, Legowska A, Rolka K, Sllberrlng J (2002) Orphanln FQ/'noclceptln but not Ro 65-6570 Inhibits the expression of cocaine-Induced conditioned place preference . Behavioural pharmacology 13 : 229-235 ; Zhao RJ, Woo RS, Jeong MS, Shin BS, Kim DG, Kim KW (2003) Orphanin FQ/noclceptln blocks methamphetamine place preference in rats. Neuroreport 14:2383-2385) and microdialysis experiments revealed that intracranial N/OFQ injection prevented cocaine from stimulating mesoaccumbal DA efflux (Lutfy K, Do T, Maidment NT (2001) Orphanin FQ/noclceptln attenuates motor stimulation and changes in nucleus accumbens extracellular dopamine induced by cocaine in rats. Psychopharmacology 154:1- 7) .
Moreover, activation of NOP receptors by N/OFQ resulted in blockade of cocaine sensitization, an effect that was absent in NOP receptor KO mice (Bebawy D, Marquez P, Samboul S, Parikh D, Hamid A, Lutfy K (2010) Orphanin FQ/nociceptin not only blocks but also reverses behavioral adaptive changes induced by repeated cocaine in mice. Biological psychiatry 68:223-230; Kotllnska J, Rafalski P, Biala G, Dylag T, Rolka K, Silberring J (2003) Nociceptin inhibits acquisition of amphetamine-induced place preference and sensitization to stereotypy in rats. European journal of pharmacology 474:233- 239; Lutfy K, Khaliq I, Carroll FT, Maidment NT (2002) Orphanin FQ/nociceptin blocks cocaine-induced behavioral sensitization in rats. Psychopharmacology 164:168-176) . It has been reported that mice lacking the NOP receptor show greater conditioned place preference for cocaine compared to wild type littermates (Marquez P, Nguyen AT, Hamid A, Lutfy K (2008) The endogenous OFQ/N/ORL-1 receptor system regulates the rewarding effects of acute cocaine . Neuropharmacology 54:564-568) .
However, the limitation of buprenorphine as potential cocaine addiction treatment is owed to its too low affinity to NOP compared with MOP (about 50 times lower) (Khroyan TV, Polgar WE, Cami-Kobeci G, Husbands SM, Zaveri NT, Toll L (2011a) . The First Universal Opioid Ligand, (2S)-2- (5R, 6R, 7R, 14S) -N- cyclopropylmethyl-4 , 5-epoxy-6, 14-ethano-3-hydro xy-6- methoxymorphinan-7-yl -3 , 3-dimethylpentan-2-ol (BU08028) : Characterization of the In Vitro Profile and In Vivo Behavioral Effects in Mouse Models of Acute Pain and Cocaine- Induced Reward. Journal of Pharmacology and Experimental Therapeutics 336(3) : 952-961) and its related abuse liability (Lavonas EJ, Severtson SG, Martinez EM, Bucher-Bartelson B, Le Lait M-C, Green JL, et al (2014) . Abuse and diversion of buprenorphine sublingual tablets and film. Journal of substance abuse treatment 47(1) : 27-34) .
Derivatives of buprenorphine with NOP/MOP activity have been prepared and tested for receptor binding affinity (Gerta Cami- Kobeci, Willma E. Polgar, Taline V Khroyan, Lawrence Toll, and Stephen M. Husbands, 2011. Structural Determinants of Opioid and NOP Receptor Activity in Derivatives of Buprenorphine . Journal of Medicinal Chemistry 54, 65-31-6537
US2008/0221141 and US2014/0303125 disclose spirocyclic cyclohexane compounds useful in pharmaceutical compositions for use in the treatment of substance dependency
WO2016/116280 discloses cebranopadol for the treatment or the prevention of pain and/or opioid drug dependence in a subject with impaired hepatic and/or renal function.
US2012034297 discloses cebranopadol for the treatment of pain. WO2016124513 discloses cebranopadol being analgesic.
US5075341 discloses buprenorphine for the treatment of cocaine abuse .
EP0432945 discloses transdermal delivery system for the treatment of cocaine or heroin addiction including buprenorphine.
Technical problem
The inventors of the present invention, in view of the findings of the prior art, investigated the involvement of NOP and MOP receptors in the cellular mechanism underlying addiction, abuse, dependence, craving, relapse to drugs and psychostimulants, in order to clarify the mechanism of action and identify new molecules useful in vanquishing drug addiction .
More in details, the same inventors investigated compounds with high affinities and strong potency to both NOP and MOP, which may have promising potential for medication of addiction, abuse, dependence, craving, relapse to drugs and psychostimulants with none, or limited, side effects.
Firstly, the same inventors clarified the role of NOP and MOP in the action of buprenorphine, which was already known for the treatment of cocaine addiction, by investigating the effect of buprenorphine on cocaine self-administration after pretreatment with the classical opioid receptor antagonist naltrexone in the presence of selective NOP antagonists, then tested small-molecule NOP agonist/MOP partial agonists and selective NOP agonist and their effect on sucrose self- administration .
Moreover, the same inventors tested the effect of cebranopadol on heroin intake and craving induced relapse, assessing its effect on heroin reinforcement and motivation by fixed and progressive ratio self-administration. Then they evaluated the effect of cebranopadol in reinstatement of heroin seeking elicited by stress or by presentations of environmental cues predictive of drug availability.
Then unexpectedly the same inventors fund that cebranopadol abolishes cocaine consumption by selectively and simultaneously targeting NOP and MOP receptors.
Object of the invention
Therefore, with reference to the attached claims and the following detailed description, the above technical problem is solved by at least one NOP/MOP receptors selective agonist molecule selected from the group consisting of: compound of general formula (I)
Figure imgf000013_0001
wherein x is halogen, H;
R is CH3, CH2CH(CH2)2, C (CH3) 3, C (CH3) 2C2H5, CH2C(CH3) CH2C ( CH3 ) 2CeH5 , p-C ( CH3 ) 3CeH4 ,
Figure imgf000013_0002
and cebranopadol with the proviso that the molecule of formula (I) is not (2S) -2- [ (5R, 6R, 7R, 14S) -17- cyclopropylmethyl-4 , 5-epoxy-6, 14-ethano-3-hydroxy-6- methoxymorphinan-7-yl] -3, 3-dimethylbutan-2-ol and 2S) -2-
(5R, 6R, 7R, 14S) -N-cyclopropylmethyl-4 , 5-epoxy-6, 14-ethano-3- hydro xy-6-methoxymorphinan-7-yl -3 , 3-dimethylpentan-2-ol , for use for the treatment of addiction and/or abuse and/or dependence and/or craving and/or relapse to drugs and/or psychostimulants .
Another object of the present invention is a pharmaceutical composition comprising a pharmacologically effective amount of at least one NOP/MOP receptors selective agonist molecule selected from the group consisting of: compound of general formula (I)
Figure imgf000014_0001
wherein x is alogen, H;
R is CH3, CH2CH(CH2)2, C (CH3) 3, C (CH3) 2C2H5, CH2C(CH3)3, CH2C ( CH3 ) 2CeH5 , p-C ( CH3 ) 3CeH4 ,
Figure imgf000014_0002
and cebranopadol with the proviso that molecule of formula (I) is not (2S)-2- [ (5R, 6R, 7R, 14S) -17-cyclopropylmethyl-4 , 5-epoxy-6, 14-ethano-3- hydroxy-6-methoxymorphinan-7-yl] -3, 3-dimethylbutan-2-ol and 2S) -2- (5R, 6R, 7R, 14S) -N-cyclopropylmethyl-4 , 5-epoxy-6 , 14- ethano-3-hydro xy-6-methoxymorphinan-7-yl -3 , 3-dimethylpentan- 2-ol, and suitable pharmaceutically acceptable excipient for use for the treatment of addiction and/or abuse and/or dependence and/or craving and/or relapse to drugs and/or psychostimulants .
Brief Description of the Drawings Figure 1 shows the effect of cebranopadol on cocaine (A) and saccharin (B) self-administration. Values are presented as mean ±SEM. Statistical differences: *p < 0.05 and ***p < 0.001 vs vehicle; #p < 0.05 and ##p < 0.01 vs 25 g/kg.
Figure 2 shows the effect of cebranopadol on motivation for cocaine expressed as breakpoint reached in SA session under a progressive ratio schedule of reforcement, data are presented as mean ± SEM. Statistical differences: *p < 0.05 vs vehicle; #p < 0.05 vs 25 g/kg.
Figure 3 shows the pharmacological mechanism by which cebranopadol decreases cocaine self-administration, for each compound administration of vehicle is indicated by the "-" mark while administration of the active agent is indicated by the "+" mark, data are presented as mean ± SEM. Statistical differences: **p < 0.01 and ***p < 0.01 vs control treatment; 00p < 0.01 and ° ° °p < 0.01 vs cebranopadol + SB-612111 + naltrexone treatment.
Figure 4 shows chronic cebranopadol treatment on cocaine self- administration. Data are presented as mean ± SEM and show the last two days pre-treatment, seven days of treatment and two days post-treatment, statistical differences: *p < 0.05, **p < 0.01, and ****p < 0.0001 vs the last day pre-treatment. Figure 5 shows the effect of cebranopadol on place conditioning test, data are presented as mean ±SEM. *p<0.05 vs control group.
Figure 6 shows the effect of cebranopadol on intravenous self- administration of different concentrations of heroin.
Figure 7 shows the results of a break point measure under progressive ratio schedule of reinforcement following administration of different doses of cebranopadol in rats self-administering heroin.
Figure 8 shows the results of Heroin-associated cues reinstated heroin seeking respect to extinction with cebranopadol .
Figure 9 shows the results of the effect of cebranopadol on stress induced reinstatement with yohimbine.
Detailed Description of the Invention
Definitions
Within the meaning of the present invention addiction and/or abuse and/or dependence to drugs and/or psychostimulants means a psychological desire to use drugs and/or psychostimulants regularly which leads to dependency and addiction.
Within the meaning of the present invention craving and/or relapse to drugs and/or psychostimulants means an intense uncontrollable desire to consume a specific drug and/or psychostimulant followed or not by resumption of its use during abstinence. Within the meaning of the present invention MOP receptor means mu-opioid (MOP) receptor.
Within the meaning of the present invention NOP receptor means nociceptin receptor, also known as the nociceptin/orphanin FQ (N/OFQ) receptor or OPRL-1 receptor or kappa-type 3 opioid receptor.
Within the meaning of the present invention agonist molecule means a chemical compound binding a receptor and activating the receptor to produce a biological response. Within the meaning of the present invention buprenorphine means (2S) -2- [ (5R, 6R, 7R, 14S) -17-cyclopropylmethyl-4, 5-epoxy- 6, 14-ethano-3-hydroxy-6-methoxymorphinan-7-yl] -3, 3- dimethylbutan-2-ol .
Within the meaning of the present invention 2S)-2- (5R, 6R, 7R, 14S) -N-cyclopropylmethyl-4, 5-epoxy-6, 14-ethano-3- hydroxy-6-methoxymorphinan-7-yl -3, 3-dimethylpentan-2-ol is also named as BU08028.
Within the meaning of the present invention (20R, 5a, 6R, 7R, 14a) -20- ( 17-Cyclopropylmethyl-7 , 8-dihydro-4, 5- epoxy-6, 14-ethano-3-hydroxy-6-methoxy-morphinan-7-yl) -40, 40- dimethylpentan-2 O-ol is also named BU08070.
Within the meaning of the present invention a pharmacologically effective amount means the dosage of the active ingredient producing a therapeutic response or desired effect without side effects.
Within the meaning of the present invention pharmaceutically acceptable excipients means any chemical alongside the active ingredient of a medication, such as, and not limited to, long- term stabilization agents, bulking agents, fillers, diluents, agents facilitating drug absorption, agents reducing viscosity, agents enhancing solubility, agents facilitating powder flowability or non-stick properties, agents aiding in vitro stability, agents preventing denaturation or aggregation, agents improving shelf life, depending also upon the route of administration and the dosage form, which can be selected by the person skilled in the art in view of his common general knowledge.
Within the meaning of the present invention drug means opioids, sedatives, hypnotics, anxiolytics, including benzodiazepines and barbiturates, cocaine, amphetamine, amphetamine-like, hallucinogens, cathinones, inhalant, polysubstance , phencyclidines , phencyclidine-like , nicotine.
Within the meaning of the present invention psychostimulant means for example amphetamines, substituted amphetamines, cocaine analogues, caffeine, methamphetamines , 3,4- Methylenedioxymethamphetamine, Methylenedioxypyrovalerone,
Mephedrone, nicotine, Propylhexedrine, Pseudoephedrine , Catha edulis (Khat) .
Object of the present invention is at least one NOP/MOP receptors selective agonist molecule selected from the group consisting of: compound of general formula (I)
Figure imgf000019_0001
wherein x is alogen, H;
R is CH3, CH2CH(CH2)2, C (CH3) 3, C (CH3) 2C2H5, CH2C(CH3) CH2C ( CH3 ) 2CeH5 , p-C ( CH3 ) 3CeH4 ,
Figure imgf000019_0002
and cebranopadol with the proviso that the molecule of formula (I) is not (2S) -2- [ (5R, 6R, 7R, 14S) -17-cyclopropylmethyl-4 , 5-epoxy 6, 14-ethano-3-hydroxy-6-methoxymorphinan-7-yl] -3, 3- dimethylbutan-2-ol and 2S) -2- (5R, 6R, 7R, 14S) -N cyclopropylmethyl-4 , 5-epoxy-6, 14-ethano-3-hydro xy-6 methoxymorphinan-7-yl -3, 3-dimethylpentan-2-ol, for use for the treatment of addiction and/or abuse and/o dependence and/or craving and/or relapse to drugs and/o psychostimulants .
Another object of the present invention is a pharmaceutical composition comprising a pharmacologically effective amount of at least one NOP/MOP receptors selective agonist molecule selected from the group consisting of: compound of general formula (I)
Figure imgf000020_0001
wherein x is alogen, H;
R is CH3, CH2CH(CH2)2, C (CH3) 3, C (CH3) 2C2H5, CH2C(CH3)3, CH2C ( CH3 ) 2CeH5 , p-C ( CH3 ) 3CeH4 ,
Figure imgf000020_0002
and cebranopadol with the proviso that the molecule of formula (I) is not (2S) -
2- [ (5R, 6R, 7R, 14S) -17-cyclopropylmethyl-4 , 5-epoxy-6, 14-ethano-
3-hydroxy-6-methoxymorphinan-7-yl] -3, 3-dimethylbutan-2-ol and 2S) -2- (5R, 6R, 7R, 14S) -N-cyclopropylmethyl-4 , 5-epoxy-6 , 14- ethano-3-hydro xy-6-methoxymorphinan-7-yl -3 , 3-dimethylpentan- 2-ol, and suitable pharmaceutically acceptable excipient for use for the treatment of addiction and/or abuse and/or dependence and/or craving and/or relapse to drugs and/or psychostimulants .
Preferably compound of formula (I) is selected from the group consisting of:
20R, 5a, 6R, 7R, 14a) -20- ( l-Bromo-17-cyclopropylmethyl-7 , 8- dihydro-4, 5-epoxy-6, 14-ethano-3-hydroxy-6-methoxymorphinan-7- yl ) -30 , 30-dimethylbutan-20-ol
20R, 5a, 6R, 7R, 14a) -20- ( 1-Chloro-l 7-cyclopropylmethyl-7 , 8- hihydro-4, 5-epoxy-6, 14-ethano-3-hydroxy-6-methoxymorphinan-7- yl ) -30 , 30-dimethylbutan-20-ol
(20R, 5a, 6R, 7R, 14a) -20- (2-Bromo-17-cyclopropylmethyl-7, 8- dihydro-4, 5-epoxy-6, 14-ethano-3-hydroxy-6-methoxymorphinan-7- yl ) -30 , 30-dimethylbutan-20-ol (10RS, 5a, 6R, 7R, 14a) -20- (17-Cyclopropylmethyl-7, 8-dihydro-3, 6- dimethoxy-4, 5-epoxy-6, 14-ethano-morphinan-7-yl ) - 30, 30- dimethylpentan-2 O-ol
(20R, 5a, 6R, 7R, 14a) -20- ( 17-Cyclopropylmethyl-7 , 8-dihydro-4, 5- epoxy-6, 14-ethano-3-hydroxy-6-methoxy-morphinan-7-yl) -30, 30- dimethylpentan-2 O-ol
(20R, 5a, 6R, 7R, 14a) -20- ( 17-Cyclopropylmethyl-7 , 8-dihydro-4, 5- epoxy-6, 14-ethano-3-hydroxy-6-methoxy-morphinan-7-yl) -40, 40- dimethylpentan-2 O-ol
(20R, 5a, 6R, 7R, 14a) -20- ( 17-Cyclopropylmethyl-7 , 8-dihydro-4, 5- epoxy-6, 14-ethano-3-hydroxy-6-methoxy-morphinan-7-yl) -40- methyl-40-phenylpentan-2 O-ol (2 OR, 5α, 6R, 7R, 14α) -10- ( 400-t-Butyl-phenyl ) -10- (17- cyclopropylmethyl-7 , 8-dihydro-4, 5-epoxy-6, 14-ethano-3-hydroxy- 6-methoxy-morphinan-7-yl ) -ethan-10-ol
(20R, 5a, 6R, 7R, 14a) -20- ( 17-Cyclopropylmethyl-7 , 8-dihydro-4, 5- epoxy-6, 14-ethano-3-hydroxy-6-methoxy-morphinan-7-yl) -10- (bicyclo[2.2.1]heptan-l-yl)-propan-20-ol
Preferably NOP/MOP receptors selective agonist molecules are selected from the group consisting of: cebranopadol and (20R, 5a, 6R, 7R, 14a) -20- ( 17-Cyclopropylmethyl-7 , 8-dihydro-4, 5- epoxy-6, 14-ethano-3-hydroxy-6-methoxy-morphinan-7-yl) -40, 40- dimethylpentan-2 O-ol or mixture thereof.
Preferably drugs and/or psychostimulants is selected from the group consisting of: opioids, sedatives, hypnotics, anxiolytics, including benzodiazepines and barbiturates, cocaine, amphetamine, amphetamine-like, hallucinogens, cathinones, inhalant, polysubstance, phencyclidines , phencyclidine-like , nicotine, substituted amphetamines, cocaine analogues, caffeine, methamphetamines , 3,4- Methylenedioxymethamphetamine, Methylenedioxypyrovalerone, Mephedrone , Propylhexedrine, Pseudoephedrine, Catha edulis (Khat) .
More preferably drug is selected from the group consisting of: heroin, cocaine.
In a preferred embodiment of the present invention cebranopadol for use for the treatment of addiction and/or abuse and/or dependence and/or craving and/or relapse to cocaine . The invention refers also to a method of treating drug addiction and/or drug abuse and/or drug dependence, preferably drug being cocaine and/or psychostimulants, dependence by administering a pharmaceutically effective dose of a NOP/MOP receptors selective agonist molecule as previously defined to a patient in need thereof.
Examples
Example 1 -mechanism of action
To shed light on The mechanism of action of NOP/MOP receptor agonist an extensive pharmacological investigation using a classical opioid receptor antagonist, NOP receptor antagonists and their combination, as well as new compounds mimicking some but not all pharmacological properties of buprenorphine was conducted .
Male Wistar rats (N=54) (Charles River, Calco, Italy) were employed. At the beginning animals' body weight ranged between 250 and 300 g. They were housed in groups of two in a room with artificial 12:12 h light/dark cycle (lights off at 9:00 a.m.), constant temperature (20-22°C) and humidity (45-55%) . All animals were handled once daily for 5 min for one week before the beginning of the experiments. During the entire period of the experimental phase, rats were offered free access to tap water and food pellets (4RF18, Mucedola, Settimo Milanese, Italy) . Experiments were conducted during the dark phase of the light/dark cycle. All procedures were performed during the dark phase and conducted in adherence to the European Community Council Directive for Care and Use of Laboratory Animals and the National Institutes of Health Guidelines for Care and Use of Laboratory Animals.
Cocaine hydrochloride was dissolved in sterile physiological saline at a concentration of .25mg/0.1 ml and given intravenously (Knoll et al . ) . Naltrexone was dissolved in distilled water and was administered intraperitoneally (IP) at the doses of 0.25, 1.0, 2.5 and 5.0mg/kg/ml 60min prior the test phase. Buprenorphine hydrochloride was administered IP at the doses of 0.3, 1.0 and 3.0mg/kg/ml 90min prior the test phase. SB-612111 was administered per os via gavage in 10.0 and 30.0mg/kg/ml 60min prior test phase. (AT-034), (AT-201) and (AT-202) (NOP/MOP agonist compounds), were synthesized by Dr. Zaveri (Astraea Therapeutics, USA) . They were administered subcutaneously (Knoll et al . ) 60 minutes prior to the test phase.
The self-administration stations consisted of operant conditioning chambers (Med Associate Inc.) enclosed in sound attenuating, ventilated environmental cubicles. Each chamber was equipped with two retractable levers located in the front panel of the chamber. A plastic tube that was connected to the catheter before the beginning of the session delivered cocaine. An infusion pump was activated by responses on the right (active) lever, while responses on the left (inactive) lever were recorded but did not result in any programmed consequences. Activation of the pump resulted in a delivery of 0.1 ml of fluid. An IBM compatible computer controlled the delivery of cocaine solution and recording of the behavioral data. Following one week of recovery from surgery rats (N=54) were trained to self-administer cocaine under a fixed ratio (FR-5) schedule of reinforcement; every 5 active lever presses resulted in the delivery of one cocaine dose (0.25 mg/ 0.1 ml, I.V.) . Following each cocaine infusion a 20 sec Time Out (TO) period was presented during which responses at the active lever had no programmed consequences.
Animals were trained to self-administer cocaine under a fixed ratio 1 (FR-1) schedule of reinforcement, for 5 consecutive days. Then they were moved to an FR-5 (with 20 sec TO) for the entire duration of the experiment. Once a stable baseline of cocaine infusion was achieved (for at least 15 consecutive days), drug treatment in a Latin square design began. Drugs were injected systemically : orally (OS), intraperitoneally (IP), or subcutaneously (SC) , 60 to 90 minutes before test began. Experiments were conducted every three days. Between drug tests cocaine self-administration baseline was reestablished. For data evaluation, the analysis of variance (ANOVA) was used followed by Newman Keuls post-hoc tests. In details, drug effects were analyzed by one factor (treatment) within subject ANOVA. A between subjects one-way ANOVA was used to analyze the data of experiment depicted in Fig 4. Experiment depicted in Fig.lC was instead analyzed by mean of a paired Student's T-test The Newman Keuls test was used for post hoc comparisons when appropriate. Statistical significance was set at * P<0.05, ** P<0.01, ***P<0.001
The results showed that Buprenorphine reduces cocaine but not saccharin self-administration in a dose-dependent manner: rats (n=8) were trained to lever press for cocaine (0.25mg/0.1 ml) under a Fixed Ratio (FR1) schedule of reinforcement. After learning acquisition, they were moved to a (FR5) schedule. Training continued until rats exhibited a stable level of responding under this contingency. Responses on the inactive lever were registered but resulted in no scheduled consequences. Rats (n=8) in a within subject counterbalanced Latin square design were then treated with buprenorphine (0.0, 0.3, 1.0, and 3.0mg/kg) given IP 90 min prior to the test phase. One-way ANOVA revealed a significant inhibition of cocaine intake following buprenorphine [F (3,7)=5.72; P <0.01]. Post Hoc Newman-Keuls analyses confirmed that buprenorphine decreased cocaine self-administration in a dose- dependent manner with the effect being significant at 0.3 mg/kg (P<0.05) and also at 1.0 and 3.0 mg/kg (P<0.01) . To control for the selectivity of the effect of buprenorphine on cocaine, another group of rats (n=6) , was trained to oral saccharin self-administration and in a within subject counterbalanced design the effect of the intermediate dose (1.0 mg/kg) of buprenorphine was tested. Paired Students t- test analysis did not show any statistically significant [t=1.44, df = 5, P=NS] effect of buprenorphine on saccharin (Fig 1C) . In both experiments, inactive lever responses was also not affected by buprenorphine [F (3, 7) =1.25; P =NS] and [t=l, df = 5, P =NS] .
The results also showed that the nonselective opioid antagonist naltrexone and the NOP antagonist SB-612111 do not reduce cocaine self-administration: in a different group of rats (n=7) trained to self-administer cocaine, the effect of a wide range of doses (0.25; 1.0; 2.5 and 5.0 mg/kg) of naltrexone on its intake was investigated. Results revealed no effect of the opioid antagonist on cocaine-related operant responding [F (4, 6) =1.416; P=NS] . Inactive lever presses was also not affected by the treatment with naltrexone [F (4, 6) =0.68; P=NS] . A second group of rats (n=9) was also trained to cocaine self-administration and the effect of the selective NOP antagonist SB-612111 (0; 10 and 30mg/kg) was explored. Also in this case results demonstrated that rats rapidly acquired a stable baseline of cocaine responding while One-way ANOVA showed no effect [F (2, 8) =0.13; P=NS] of SB- 612111 on its intake. Inactive lever was not affected by the treatment. [F (2,8)=0.58; P=NS] .
Was also demonstrated that pre-treatment with naltrexone or SB-612111 does not block the effect of buprenorphine on cocaine self-administration. To evaluate the role of MOP and NOP receptors in mediating buprenorphine induced-reduction of cocaine self-administration, the effect of naltrexone (0.25, 1 and 2.5mg/kg), SB-612111 (10 and 30mg/kg) and their combination against buprenorphine was tested. Naltrexone was administered 30 min prior to buprenorphine (lmg/kg) and 90 min later rats (n=10) were tested for cocaine self-administration . The experiment was carried out in a within subject Latin square counterbalance design. One-way ANOVA revealed a statistically significant overall effect of treatment [F (4, 9) =11.94; P <0.0001] on cocaine self-administration. Post Hoc Newman-Keuls comparison indicated that buprenorphine (1 mg/kg) alone significantly decreased cocaine self- administration compared to vehicle treated rats (P<0.001) . Treatment with naltrexone did not alter cocaine self- administration per se either it counteracted the inhibitory effect of buprenorphine on cocaine self-administration. Responses on the inactive lever were not influenced [F (4, 9) =1.55; P = NS] by treatments. The same effect was observed when the NOP receptors were selectively blocked by SB-612111, 30 min prior buprenorphine administration. Overall ANOVA yield a statistically significant effect of the treatment: [F (3,8)=50.04; P <0.0001]. Post Hoc Newman-Keuls analysis indicate that buprenorphine by itself significantly decreased cocaine self-administration compared to the control group (buprenorphine 1.0 mg/kg vs Vehicle P<0.001) . On the other hand, SB-612111 alone did not alter cocaine self- administration compared to the control group, nor affected buprenorphine induced reduction of cocaine self-administration (P>0.05) . The responses on the left lever were not influenced by the treatment [F (3,8)=0.37; P = NS] .
The results underlined that the combination of naltrexone and SB-612111 block the effect of buprenorphine on cocaine self- administration. NOP and MOP receptors were simultaneously blocked by concomitant administration of SB-612111 (30mg/kg) and naltrexone (2.5mg/kg), given prior to buprenorphine (lmg/kg) . One-way ANOVA revealed a significant overall effect of treatment: [F (4, 45) =34.30; P<0.0001]. Post Hoc Newman- Keuls comparisons indicated that animals treated directly with buprenorphine, significantly (P<0.001) reduced the intake of cocaine. The same effect was observed in the animals treated with SB-612111 or naltrexone alone prior to buprenorphine. Interestingly however, cocaine self-administration was significantly inhibited by simultaneous treatment with naltrexone and SB-612111 (P<0.001) suggesting that concomitant inhibition of both receptors is required to attenuate cocaine self-administration. Treatment with SB-612111 and naltrexone in combination did not affect cocaine intake. Moreover, no drug effects were observed at the inactive control lever. The results showed that buprenorphine-like (AT-034) and (AT- 201) but not N/OFQ-like compound (AT-202) selectively reduces cocaine self-administration . Separate groups of rats (n=7-9) were trained to self-administer cocaine and saccharin solutions in operant chambers. (AT-034), (AT-201) and (AT-202) (1.0; 3.0 and 10 mg/kg), were administered 60 min prior the test phase. Experiments were carried out in a within subject Latin square counterbalance design. One-way ANOVA revealed a statistically significant overall effect of (AT-034) on cocaine self-administration [F (3,6)=4.47; P <0.01]. Post Hoc Newman-Keuls comparisons indicated that (AT-034) at 3.0 and 10.0 mg/kg significantly reduced cocaine self-administration compared to controls (P<0.05) . ANOVA also revealed a statistically significant effect of (AT-034) on saccharin self-administration [F (3,8)=9.13; P <0.001]. Post hoc comparisons revealed a significant (P<0.001) inhibition of saccharin at 10 mg/kg suggesting lack of specificity at this dose. Treatment did not affect inactive lever responses either for cocaine [F (3, 6) =0.73; P=NS] (Fig 5B) or saccharin [F (3, 8) =2.8; P=NS] . For (AT-201), one-way ANOVA revealed an overall statistically significant effect of treatment: [F (3, 6) =4.57; P<0.05]. Post hoc Newman-Keuls comparisons indicated that (AT-201) significantly reduced cocaine self- administration at 3.0 mg/kg (P<0.05) and 10.0 mg/kg (P<0.05) compared to the vehicles. ANOVA also revealed a statistically significant [F (3, 7 ) =14.01; P<0.0001] effect of (AT-201) on saccharin self-administration. Post hoc Newman-Keuls test revealed that compared to controls, (AT-201) significantly reduced saccharin self-administration at the highest dose tested, 10.0 mg/kg (P<0.001) . The treatment with (AT-201) did not affect inactive lever responses for cocaine [F (3, 6) =0.13; P=NS] or saccharin [F (3,7)=0.5; P=NS] . For (AT-202), one-way ANOVA failed to reveal an overall significant effect of treatment on cocaine self-administration [F (3, 8) =2.96; P=NS] as well as on saccharin self-administration [F (3,8)=0.37; P=NS] . The treatment with (AT-202) did not affect inactive lever responses for cocaine [F (3, 8) =2.5; P=NS] or saccharin [F (3,8)=1.57; P=NS] The results demonstrated that buprenorphine dose dependently reduced operant responding for cocaine and the effect was selective since, over the same dose range, buprenorphine did not affect saccharin self-administration. Importantly the results showed that blockade of classical MOP, DOP and KOP by naltrexone or selective inhibition of NOP receptors by SB- 612111 was not sufficient to prevent the inhibitory action of buprenorphine on cocaine self-administration, supporting that the inhibitory effect of buprenorphine on cocaine intake is due to its ability to simultaneously activate MOP and NOP receptors. This was confirmed by co-administration of naltrexone and SB-612111 prior to buprenorphine, completely blocking the inhibitory effect of buprenorphine on cocaine self-administration. These findings was strengthened by the tests conducted on small-molecule compounds with a range of affinities and selectivity for MOP, KOP, and NOP receptors: (AT-201) (previously called SR16435) which is a high affinity partial agonist at NOP and MOP receptors, (AT-034) which is a moderate affinity partial agonist at NOP but is a high affinity agonist at MOP, and (AT-202) (previously called SR16835) that is a high affinity and potent NOP agonist with moderate affinity and partial agonist activity at MOP. Results showed that (AT-034) and (AT-201) attenuated cocaine self- administration but at the highest dose (10 mg/kg) the two compounds also reduced saccharin self-administration whereas at lower dose (3 mg/kg) their effect was selective for cocaine. The full NOP agonist (AT-202) given at pharmacologically effective doses did not show effects on cocaine and saccharin intake. Together these findings showed that at low doses the effect of these agents is specific for cocaine indicating that concomitant activation of MOP and NOP attenuate psychostimulant reinforcement, and that the efficacy in preventing cocaine intake is linked to a specific balance between MOP and NOP affinity and efficacy with highest effects achieved following partial agonism at both receptors. In fact, (AT-202) that acts as a full agonist at NOP appeared to have no effect on cocaine self-administration . In addition, the experiments demonstrated that the efficacy of (AT-034) and (AT-201) in reducing cocaine intake was comparable to that of buprenorphine , whereas their binding at KOP receptor was about 20 and 60 times lower, respectively, which further discourages the hypothesis of an involvement of KOP receptors in mediating the effects observed here on cocaine self-administration.
The evidences provided support the hypothesis according to which buprenorphine blunts the motivation for cocaine by simultaneously activating MOP and NOP receptors.
Example 2 - Cebranopadol
Male Wistar rats (Charier River, Italy) , weighing 270-320 g at the beginning of the experiments were used. Pairs of rats were housed in a room with artificial 12/12 h light/dark cycle (lights off at 8 am) , at constant temperature (20-22°C) and humidity (45-55%) . Food (4RF18, Mucedola, Settimo Milanese, Italy) and water were provided ad libitum except during session time. All the experiments were conducted during the dark phase of the light/dark cycle. Rats were allowed to acclimate to the housing room for one week and were handled 3 times before any experimental manipulation. All the procedures were carried out in accordance with the European Community Council directive and the National Institutes of Health guidelines for the care and use of laboratory animals.
Cocaine hydrochloride and morphine hydrochloride (Sigma, USA) were dissolved in sterile saline. Saccharin (Sigma, Italy) was dissolved in tap water. Cebranopadol (Biochempartner Co., Ltd, China) for operant tests was dissolved with 5% DMSO and 95% glucose (5%) . Cebranopadol for place conditioning was dissolved in 10% DMSO + 5% Cremophor EL + 85% saline. The selective NOP antagonist SB-612111 was kindly provided by Eli Lilly (USA) ; it was dissolved in 1 M H3P04 in distilled water (1:1) . MOPr antagonist naltrexone (Sigma, USA) was dissolved in distilled water.
The self-administration (SA) stations consisted of operant conditioning chambers (Med Associate Inc.) enclosed in sound attenuating, ventilated environmental cubicles. Each chamber was equipped with two retractable levers located in the front panel of the chamber. A plastic tube that was connected to the catheter before the beginning of the session delivered cocaine. An infusion pump was activated by responses on the right (active) lever, while responses on the left (inactive) lever were recorded but did not result in any programmed consequences. Activation of the pump resulted in a delivery of 0.1 ml of fluid. An IBM compatible computer controlled the delivery of cocaine solution and recording of the behavioral data .
Rats (n = 16) were initially trained to a 2-h daily cocaine SA sessions under Fixed Ratio 1 (FR1) schedule of reinforcement for 10 days, then reinforcement schedule was increased to FR5 until stable baseline of responding (less 10% variation for 3 consecutive days) was reached. Following each cocaine infusion (0.25 mg/ 0. lml intra-venous ) , a 20 sec Time Out (TO) period was presented during which responses at the active lever had no programmed consequences. Cebranopadol (0, 25, 50 g/kg per os (p.o.) lh before test) was tested in a Latin square counterbalanced design. At least 3 days interval during which cocaine self-administration baseline was re-established was allowed between drug tests.
For progressive ratio (PR) experiments, the response requirements necessary to receive a single cocaine dose increased according to the following scale: 5, 11, 18, 26, 35, 45, 56, 68, 82, 98, 116, 136, 158, 182, 208, 236, 268, 304. PR session stopped after 6 hours or if the required ratio was not achieved within 1 hour, whichever came first. The breakpoint (BP) , corresponding to the last ratio completed was used as a measure of motivation. One hour before test, rats (n = 8) were treated with cebranopadol (0, 25, 50 g/kg p.o.) in a Latin square counterbalanced design. Drug treatment was performed every fourth day. Baseline FR5 cocaine self-administration was re-established between PR tests. Another group of rats (n = 8) was used to test the effect of cebranopadol on oral saccharin (0.2% w/v) self-administration . Rats were trained to 30 min daily sessions under a FR1 schedule of reinforcement until stable lever pressing baseline was reached. At this point, in a Latin square counterbalanced design the effect of cebranopadol (0, 25, 50 g/kg p.o.) was tested. Drug treatment was performed every fourth day one hour before test. Baseline FR1 saccharin self-administration was re-established between tests.
To evaluate if the effect of cebranopadol on cocaine intake is subjected to tolerance development the effect of sub-chronic cebranopadol treatment was tested. For 7 consecutive days two groups of rats (n = 7-8/group) with similar cocaine self- administration baseline were treated with cebranopadol (25 g/kg p.o.) or its vehicle given 1 hour before initiating the 2-h self-administration sessions under FR5. To explore the mechanisms of action of cebranopadol here we tested the effect of the selective NOP antagonist SB-612111 (SB, 30 mg/kg p.o.), the MOP/KOP/DOP antagonist naltrexone (Nal, 2.5 mg/kg intra-peritoneally (i.p.)) or their combination on cebranopadol-induced inhibition of cocaine self-administration (Zaratin et al, 2004; Zhang et al, 2013) . One hour before session, rats (n = 10) received cebranopadol (50 g/kg p.o.) or its vehicle alone or in combination with SB-612111 and Naltrexone or both antagonists together. Rats were subjected to all treatment condition in a Latin square design. At least 3 days interval during which cocaine self- administration baseline was re-established was allowed between drug tests.
To test whether cebranopadol has rewarding effects per se, we measured place conditioning induced by cebranopadol in a two compartment apparatus using an unbiased schedule of conditioning. Rats (n = 8/group) underwent one 25 minutes conditioning session per day for six days. Cebranopadol groups (10 and 50 g/kg i.p) received three cebranopadol treatments in one compartment or three vehicle treatments in the opposite compartment every other day. The control group received vehicle injections in both compartments. Treatments were balanced across compartments and days. On the 7th day, drug free animals were allowed to explore the entire apparatus for 15 min. Time spent in each compartment was recorded by an operator unaware of treatment conditions. Rats received treatments 15 minutes before session.
To check whether our protocol is suitable to assess opioid- induced place conditioning, as a positive control we treated a group of rats (n=7) with morphine (5 mg/kg i.p.) with the same conditioning schedule. Rats received treatments 5 minutes before session.
The effect of acute cebranopadol on cocaine and saccharin self-administration as well as the effect of NOP and MOP antagonist on cebranopadol-induced reduction of cocaine infusions was analyzed by one way ANOVA with treatment as repeated measure. The effect of chronic cebranopadol on cocaine self-administration was analyzed by two-way ANOVA with one factor between (treatment) and one factor within (time) . Inactive level responses were separately analyzed and used as an additional measure to monitor the specificity of drug effects. The Newman Keuls test was used for post hoc analysis when appropriate. To analyze place conditioning, to verify that our protocol was unbiased, we used t-test for dependent samples to compare the time spent by control rats in each compartment. Preference score was defined as the time spent in the drug-paired compartment minus the time spent in the vehicle-paired compartment. For the control group, as they received vehicle in both compartments and they did not show preference for either of the compartments, preference score was computed subtracting the time spent in compartment A to the time spent in compartment B for half of the rats and vice versa for the other half. We analyzed Morphine place conditioning by t-test for independent groups (vehicle vs morphine) . We analyzed Cebranopadol place conditioning by oneway ANOVA with groups as independent factors (cebranopadol: 0, 10 and 50 g/kg) . Results were expressed as mean ± SEM and statistical significance was set as: p < 0.05.
The text showed that cebranopadol selectively reduced cocaine self-administration, since rats rapidly acquired a stable baseline of cocaine responding under FR5 contingency. ANOVA revealed an overall significant [Infusions: F(2, 7) = 13.77, p
< 0.0001,; Active lever: F (2, 7) = 8.161, p 0.005] effect of cebranopadol on cocaine self-administration. Post hoc analysis revealed a highly significant inhibition in the number of cocaine reinforced responding at both doses of cebranopadol tested (***p < 0.001) . Inactive lever pressing was very low and was not affected by drug treatment [F (2, 7) =0.9143, p = 0.4234] . The above results are shown in figure 1.
When the effect of cebranopadol was evaluated under PR contingency, overall ANOVA confirmed a highly significant reduction in the motivation for cocaine [F(2, 7) = 6.915, p = 0.0082]. Post hoc tests indicated a significant reduction (*p
< 0.05) following administration of the highest dose (50 g/kg) of the drug. Identical effect was confirmed in the active lever responses [F (2, 7) = 5.114, p = 0.0215, Fig. 2B] while inactive lever respondings were low and not altered [F (2, 7) = 0.8534, p = 0.4470] . The results are shown in figure 2.
Further experiments demonstrated that acute cebranopadol selectively increased saccharin self-administration: rats rapidly acquired saccharin self-administration under FR1 contingency. ANOVA revealed an overall significant [Infusions: F (2, 7) = 4.859, p = 0.0250, Fig. IB; Active lever: F (2, 7) = 9.789, p = 0.0022] increase in saccharin self-administration following cebranopadol treatment. Post hoc analysis showed a significant increment (*p < 0.05) in operant responding for the sweet solution following administration of 25 g/kg of cebranopadol. At a higher dose (50 g/kg) the drug did not modify saccharin self-administration . Inactive lever pressing was very low and was not affected by drug treatment [F (2, 7) = 2.223, p = 0.1451] . Moreover chronic cebranopadol reduces cocaine self- administration without development of tolerance, ANOVA revealed an overall significant [F (1, 13) = 1.16832, p = 0.299392] effect of chronic treatment with cebranopadol on cocaine infusions under FR5 contingency. No effect of time was detected [F (9, 117) = 4.75441, p = 0.000021]. However, the inhibitory effect of cebranopadol slightly increased over treatment days which resulted in a significant treatment x time interaction [F (9, 117) = 4.46698, p = 0.000047]. As shown in Fig. 3A, in post hoc tests no significant differences were detected during the first three treatment days. Whereas a significant inhibition in the number of cocaine reinforced responding was detected on days 4 and 7 (*p < 0.05) and a very significant reduction on days 4, 5 and 6 (**p < 0.01, ***p < 0.001) . When inactive lever responding was analyzed ANOVA revealed no effect of treatment [F (1, 13) = 0.45985, p = 0.50958] and time [F (9, 117) = 0.931202, p = 0.50110], active lever, Treatment: F (1, 13) = 0.01726, p = 0.89750, Time: F (9, 117) = 4.2027, p = 0.00010, Interaction: F (9, 117) = 3.0689, p = 0.00245. The results are shown in figure 3.
To investigate the pharmacological mechanism by which cebranopadol inhibits cocaine intake the effect SB-612111, a selective NOP antagonist, and of naltrexone a preferential MOP antagonist on cebranopadol-induced inhibition of cocaine self- administration was tested. ANOVA revealed an overall effect of treatment [Infusions: F (4, 9) = 8.756, p < 0.0001; Active lever: F (4, 9) = 4.197, p = 0.0068,]. Newman Keuls post hoc test confirmed that 50 g/kg cebranopadol significantly reduced the number of cocaine reinforced responding (***p < 0.001) . Neither SB-612111 nor Naltrexone alone were able to antagonize cebranopadol effect. In contrast, when SB-612111 and Naltrexone were co-administered they completely reversed cebranopadol-induced reduction of cocaine self-administration (##p < 0.01) . Inactive lever responding was very low and as shown by overall ANOVA was never affected by treatments [F (4, 9) = 1.225, p = 0.3172], the above results are shown in figure 4.
Control rats did not show preference for either of the compartments, demonstrating that we performed place conditioning in unbiased conditions [t(8)=0.44; p=0.67]. Morphine treated rats showed positive, and higher than control, preference score [t (13) =-2.33; p=0.37], demonstrating that our protocol was suitable to test place preference induced by drugs targeting the opioid system (Fig. 5 inset) . ANOVA of cebranopadol place conditioning found no overall effect of groups [ F (2.21 ) =1.83; p=0.18], indicating that cebranopadol did not induce place conditioning (Fig. 5) .
The performed experiments show that cebranopadol significantly reduced cocaine self-administration under fixed and progressive ratio schedule of reinforcements indicating reduced motivation for cocaine following drug treatment. The effect was substance-specific because when ceranopadol was tested on saccharin self-administration, at the lowest dose it slightly increased the intake and at highest one it left the intake unchanged. The tendency of cebranopadol to increase the consumption of sweet solutions is consistent with its ability to activate MOP receptors. The inhibitory effect of cebranopadol on cocaine self-administration was increased during chronic treatment, suggesting that following repeated drug administrations this effect is not subjected to development of tolerance. The inhibitory effect of cebranopadol on cocaine self-administration is blocked by coadministration of SB-612111 and naltrexone, which indicates that co-activation of MOP and NOP is an essential step mediating this drug action. Cebranopadol does not elicit place preference. Cebranopadol is a high affinity agonist at both MOP and NOP receptors and is almost equipotent in activating both receptors.
Example 3 - heroin
Experiments were performed in male Wistar rats (Charles River Laboratories) weighting 280-330g at the beginning of the experiments . Rats were housed two per cage in a room with a reverse 12:12 h light/dark cycle (lights off at 9:00 a.m.), constant temperature (20-22°C) and humidity (45-55%) . All animals were allowed to acclimate to the housing room for one week and were handled once daily for 5 min for one week before the beginning of the experiments. During the entire period of the experimental phase, rats were offered ad libidum access to tap water and food pellets (4RF18, Mucedola, Settimo Milanese, Italy) . Experiments were conducted during the dark phase of the light/dark cycle. All the procedures were in accordance with the European Community Council Directive for Care and Use of Laboratory Animals and the National Institutes of Health Guidelines for Care and Use of Laboratory Animals. Heroin (SALARS, Como, Italy) was dissolved in sterile saline solution and self-administered intra-venous by the rats at the doses of 7, 20, and 60 g/infusion, self-administration volume was of 0.1 ml/infusion. Yohimbine Hydrochloride (Sigma, Italy) was dissolved in millipore water and injected intraperitoneally (1,25 mg/kg/ml) 30 minutes before sessions. Cebranopadol (Biochempartner Co., Ltd, China) was dissolved in 10%DMSO + 5%cremophor EL + 85%saline, administered orally 1 hour before test sessions. To make rats familiar with treatment process, before tests session, rats were injected by gavage with tap water. Self-administration chambers and apparatuses were the same used to study cocaine self-administration. Animals were catheterized into the right jugular vein as described above in the cocaine study. Rats were allowed to recover one week before the beginning of self-administration (SA) training. Catheters' patency was confirmed by intravenous injection of 150 μΐ of pentothal sodium (25 mg/ml, Intervet, Italy) . Before each SA session catheters were flushed with 100 μΐ of heparinized saline (20 U.I. /ml) containing 0.5 mg/ml of enrofloxacin per rat.
Following one week of recovery from surgery rats were trained to 2h daily heroin SA sessions, where active lever pressing under a fixed ratio (FR-1) schedule was reinforced with 20 g/infusion of heroin. Each heroin infusion was followed by a 20 sec time out period during which responses at the active lever had no programmed consequences. During heroin self- administration beep was always on and cue light was on for 20 seconds when active lever was pressed.
After completion of the training phase, all the animals reached a stable heroin self-administration baseline. At this point, 30 rats were used to test the effect of cebranopadol on heroin self-administration both in a fixed ratio and in a progressive ratio schedule of reinforcement.
For fixed ratio, rats were initially trained to a 2-h daily heroin SA sessions under Fixed Ratio 1 (FR1) schedule of reinforcement for 15 or 27 days until stable baseline of responding (less 10% variation for 3 consecutive days) was reached. Rats were then divided in three sub-groups (n=10 each) each self-administering a different dose of heroin (7, 20, 60 g/infusion) . After 5 days of baseline training with the new doses, the effect of Cebranopadol (0, 25, 50 g/kg) on heroin SA was tested in a Latin square counterbalanced design. At least 3 days interval during which heroin self- administration baseline was re-established was allowed between drug tests.
For progressive ratio, the same animals were used for progressive ratio (PR) tests, in which the response requirements necessary to receive a single heroin dose increased according to the following scale: 1, 2, 4, 6, 9, 12, 15, 20, 25, 32, 40, 50, 62, 77, 95, 118, 145, 178, 219, 268. PR session stopped after 4 hours or if the required ratio was not achieved within 1 hour, whichever came first. The breakpoint (BP) , corresponding to the last ratio completed, was used as a measure of motivation. In this experiment rats (n = 9-10) were tested with cebranopadol (0, 25, 50 g/kg) in a Latin square counterbalanced design. Drug treatment and PR tests were performed every fourth day. Baseline FR1 heroin SA was re-established between PR tests.
Then the effect of cebranopadol on cue-induced reinstatement of heroin seeking was investigated in 12 rats. The experiment consisted of three phases.
The first phases was the discrimination training. The purpose of this phase was to train rats to self-administer heroin while simultaneously establishing discriminative stimuli associated with heroin availability vs non-availability. Once stable heroin SA baseline was established as describe for experiment-1 (heroin dose 20 g/infusion) , rats were subjected to discrimination learning as follow. In three daily lh sessions, either heroin or saline was available as the only infusion solution. Each day include one saline and two heroin sessions conducted in random order. Sessions were initiated by the extension of the lever and presentation of the respective discriminative stimulus, which remained on for the entire duration of the session. Discriminative stimulus associated with heroin availability was an intermittent beep tone while that associated with saline was the continuous illumination of the self-administration chamber by the house light. Both heroin and saline infusions were followed by 20s timeout. Timeout was signalled by illumination of the cue-light for heroin and by a white noise for saline. Discrimination training regime was maintained for 20 days. Before every saline session, catheters were flushed with heparinized solution to prevent the heroin left-over in the dead volume of the catheter to reinforce the first infusion of the saline session .
The second phase was the extinction training, following the discrimination, and consisting of 1 hour daily session during which active lever pressing activated the syringe pump motor but no fluid was delivered, and discriminative and discrete stimuli were not presented.
The third phase was the cue-induced reinstatement and Cebranopadol treatment, wherein the reinstatement tests began the day after the last extinction session. This test lasted lh under conditions identical to those during the discrimination phase, except that heroin and saline were not made available. Rats were tested under the saline-paired condition on day one and from day two they were tested for cue-induced reinstatement of heroin seeking by re-exposure to heroin- paired stimuli. One hour before cue-induced reinstatement of heroin seeking tests rats were treated with cebranopadol (0, 25, 50 g/kg) doses administered in counterbalanced order. Cebranopadol was administered by gavage . Responses at both active and inactive levers were recorded. Between tests rats remained in their home-cages .
Moreover, the effect of cebranopadol on yohimbine-induced heroin relapse was investigated in 11 rats and it consisted of three phases. The first phase was the self-administration training, wherein the rats were trained to 2-h daily heroin SA as described before. The second phase was the extinction training wherein, after training, rats entered the extinction phase where they run 1 hour daily for 10 days. During extinction, active lever pressing activated the syringe pump motor but did not result in fluid delivery. The third phase was yohimbine-induced reinstatement of heroin seeking. Yohimbine-induced reinstatement session was similar to a standard extinction session, except that 1 hour prior to test rats were orally administered with cebranopadol (0, 25, 50 g/kg) and 30min later they received an intraperitoneal injection of yohimbine ( 1.25mg/kg/ml ) . Tests were repeated every fourth day and cebranopadol doses were administered in counterbalanced order. Between tests rats performed standard extinction training between sessions. Rats rapidly acquired heroin SA and maintained stable responding at the different doses (7, 20, 60 ]ig , as shown in figure 6. ANOVA revealed an overall effect of cebranopadol doses for each heroin SA subgroup (7 g/kg: [F (2, 9) = 25.19, p < 0.0001]; 20 g/kg: [F (2, 9) = 16.78, p < 0.0001]; 60 g/kg: [F (2, 8) = 3.664, p < 0.05]) . Newman-Keuls post-hoc analysis indicated that Cebranopadol at the dose of 50 g/kg decreased self- administration for each of the three heroin doses, while the dose of 25 g/kg decreased the number of infusions earned only at heroin doses of 7 and 20 g/infusion, as shown in figure 6. Then was tested the effect of cebranopadol on motivation for heroin scored by the break point in a PR session. ANOVA revealed an overall effect of cebranopadol only for the dose of 60 g/kg (7 g/kg: [ F (2, 9) = 0.1179, p = NS] , 20 g/kg: [F (2, 9) = 2.785, p = NS] , 60 g/kg: [F (2, 8) = 15.84, p < 0.001]. Newman-Keuls post-hoc analysis indicated that both doses of cebranopadol decreased break-point for 60 g/infusion of heroin, as shown in figure 7.
In addition, the effect of cebranopadol on cue-induced reinstatement of heroin seeking was investigated. After 20 days of training, animals discriminated between saline and heroin so that responding for heroin was higher than saline, which responding decreased over time. Abnimals were then subjected to an extinction training during which lever responding progressively decreased. At this point rats were subjected to a cue-induced reinstatement test. Cebranopadol was given 1 hour prior to the beginning of the relapse test. ANOVA revealed an overall effect of treatment [F(3, 33) = 4.37541, p < 0.01] and lever by treatment interaction [F (3, 33) = 4.55838, p < 0.01]. Newman-Keuls as post-hoc analysis revealed that re-exposure to heroin-predictive cues reinstated heroin seeking and the dose of 50 g/kg of cebranopadol reduced cue-induced heroin seeking. Both cue and cebranopadol effect were specific for active lever as inactive was always very low and not affected by experimental conditions, as shown in figure 8.
To test the effect of cebranopadol on stress induced reinstatement, the pharmacological stressor yohimbine, a alfa- 2 antagonist commonly used in addiction research, was used to evaluate the contribution of stress in addiction behaviour. Rats were maintained under self-administration training regimen for 27 day during which the number of infusion of heroin earned in each session gradually increased. Then rats where switched to the extinction protocol, during which responding on the active lever gradually decreased. When lever responding was extinguished we run yohimbine-induced reinstatement test. ANOVA revealed an overall effect of treatment [F (3, 27) = 3.3281, p < 0.05]. Newman-Keuls post- hoc analysis showed that yohimbine reinstated lever pressing compared to extinction, and that cebranopadol at the dose of 50 g/kg abolished yohimbine-induced reinstatement, as shown in figure 9.
The above results showed that, after treatment with cebranobadol (25 e 50 mg/kg) rats self-administered less heroin both under a fixed ratio 1 and a progressive ratio schedule of reinforcement compared. The effect was significant for both does tested under a fixed ratio when the amount of heroin infused was 7 and 20 g/infusion. On the contrary, in the progressive ratio, only the higher dose of cebrabopadol is effective for a 60 g/infusion of heroin. The evaluation of the effect of cebranopadol on yohimbine and cue-induced reinstatement of heroin seeking revealed that cebranopadol is efficacious not only in treating withdrawal in opioids dependent subjects but is also attenuates opioid consumption and reduces the risks of relapse in abstinent previously heroin users.

Claims

1) At least one NOP/MOP receptors selective agonist molecule selected from the group consisting of:
compound of general formula (I)
Figure imgf000046_0001
wherein x is alogen, H;
R is CH3, CH2CH(CH2)2, C (CH3) 3, C (CH3) 2C2H5, CH2C (CH3) 3, CH2C ( CH3 ) 2CeH5 , p- C(CH3)3C6H4,
Figure imgf000046_0002
and cebranopadol with the proviso that the molecule of formula (I) is not (2S) -2- [ (5R, 6R, 7R, 14S) -17-cyclopropylmethyl-4 , 5-epoxy- 6, 14-ethano-3-hydroxy-6-methoxymorphinan-7-yl] -3, 3- dimethylbutan-2-ol and 2S)-2- (5R, 6R, 7R, 14S) -N- cyclopropylmethyl-4 , 5-epoxy-6, 14-ethano-3-hydro xy-6- methoxymorphinan-7-yl -3, 3-dimethylpentan-2-ol, for use for the treatment of addiction and/or abuse and/or dependence and/or craving and/or relapse to drugs and/or psychostimulants.
2) At least one NOP/MOP receptors selective agonist molecule for use for the treatment of addiction and/or abuse and/or dependence and/or craving and/or relapse to drugs and/or psychostimulants according to claim 1 wherein compound of formula (I) is selected from the group consisting of: 20R, 5a, 6R, 7R, 14a) -20- ( l-Bromo-17-cyclopropylmethyl-7 , 8- dihydro-4, 5-epoxy-6, 14-ethano-3-hydroxy-6- methoxymorphinan-7-yl ) -30 , 30-dimethylbutan-20-ol
20R, 5a, 6R, 7R, 14a) -20- ( 1-Chloro-l 7-cyclopropylmethyl-7 , 8- hihydro-4, 5-epoxy-6, 14-ethano-3-hydroxy-6- methoxymorphinan-7-yl ) -30 , 30-dimethylbutan-20-ol
(20R, 5a, 6R, 7R, 14a) -20- (2-Bromo-17-cyclopropylmethyl-7, 8- dihydro-4, 5-epoxy-6, 14-ethano-3-hydroxy-6- methoxymorphinan-7-yl ) -30 , 30-dimethylbutan-20-ol
(10RS, 5a, 6R, 7R, 14a) -20- (17-Cyclopropylmethyl-7, 8- dihydro-3, 6-dimethoxy-4 , 5-epoxy-6, 14-ethano-morphinan-7- yl)- 30 , 30-dimethylpentan-20-ol
(20R, 5a, 6R, 7R, 14a) -20- ( 17-Cyclopropylmethyl-7 , 8-dihydro- 4 , 5-epoxy-6, 14-ethano-3-hydroxy-6-methoxy-morphinan-7- yl) -30, 30-dimethylpentan-20-ol
(20R, 5a, 6R, 7R, 14a) -20- ( 17-Cyclopropylmethyl-7 , 8-dihydro- 4 , 5-epoxy-6, 14-ethano-3-hydroxy-6-methoxy-morphinan-7- yl) -40, 40-dimethylpentan-20-ol (20R, 5α, 6R, 7R, 14α) -20- ( 17-Cyclopropylmethyl-7 , 8-dihydro- 4 , 5-epoxy-6, 14-ethano-3-hydroxy-6-methoxy-morphinan-7- yl ) -40-methyl-40-phenylpentan-20-ol
(2 OR, 5a, 6R, 7R, 14a) -10- ( 400-t-Butyl-phenyl ) -10- (17- cyclopropylmethyl-7 , 8-dihydro-4, 5-epoxy-6, 14-ethano-3- hydroxy- 6-methoxy-morphinan-7-yl ) -ethan-10-ol
(20R, 5a, 6R, 7R, 14a) -20- ( 17-Cyclopropylmethyl-7 , 8-dihydro- 4 , 5-epoxy-6, 14-ethano-3-hydroxy-6-methoxy-morphinan-7- yl) -10- (bicyclo [2.2. l]heptan-l-yl) -propan-2 O-ol 3) At least one NOP/MOP receptors selective agonist molecule for use for the treatment of addiction and/or abuse and/or dependence and/or craving and/or relapse to drugs and/or psychostimulants according to claim 1 wherein the NOP/MOP receptors selective agonist molecule is selected from the group consisting of: cebranopadol and (20R, 5a, 6R, 7R, 14a) -20- (17-Cyclopropylmethyl-7, 8- dihydro-4, 5-epoxy-6, 14-ethano-3-hydroxy-6-methoxy- morphinan-7-yl ) -40, 40-dimethylpentan-2 O-ol or mixture thereof .
4) At least one NOP/MOP receptors selective agonist molecule for use for the treatment of addiction and/or abuse and/or dependence and/or craving and/or relapse to drugs and/or psychostimulants according to anyone of claims 1-3 wherein drug and/or psychostimulant is selected from the group consisting of opioids, sedatives, hypnotics, anxiolytics, including benzodiazepines and barbiturates, cocaine, amphetamine, amphetamine-like, hallucinogens, cathinones, inhalant, polysubstance, phencyclidines , phencyclidine-like , nicotine, substituted amphetamines, cocaine analogues, caffeine, methamphetamines , 3,4-
Methylenedioxymethamphetamine,
Methylenedioxypyrovalerone , Mephedrone , Propylhexedrine, Pseudoephedrine , Catha edulis (Khat) .
At least one NOP/MOP receptors selective agonist molecule for use for the treatment of drug addiction and/or drug abuse and/or drug dependence according to anyone of claims 1-4 in a pharmaceutical composition comprising a pharmacologically effective amount of at least one NOP/MOP receptors selective agonist molecule and pharmaceutically acceptable excipients.
At least one NOP/MOP receptors selective agonist molecule for use for the treatment of addiction and/or abuse and/or dependence and/or craving and/or relapse to drugs and/or psychostimulants according to anyone of claims 1-5 wherein the NOP/MOP receptors selective agonist molecule is cebranopadol for use for the treatment of addiction and/or abuse and/or dependence and/or craving and/or relapse to cocaine.
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