WO2014022143A1 - Antagoniste du récepteur orl-1 pour le traitement de l'anxiété - Google Patents

Antagoniste du récepteur orl-1 pour le traitement de l'anxiété Download PDF

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Publication number
WO2014022143A1
WO2014022143A1 PCT/US2013/051575 US2013051575W WO2014022143A1 WO 2014022143 A1 WO2014022143 A1 WO 2014022143A1 US 2013051575 W US2013051575 W US 2013051575W WO 2014022143 A1 WO2014022143 A1 WO 2014022143A1
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methyl
chloro
anxiety
fluoro
disorder
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PCT/US2013/051575
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English (en)
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Michael Angelo Statnick
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Eli Lilly And Company
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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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61P25/22—Anxiolytics

Definitions

  • the present invention relates to the use of Nociceptin/orphanin FQ receptor (NOC/OFQ) antagonists, specifically ORL-1 receptor antagonists, for the treatment of anxiety disorders.
  • NOC/OFQ Nociceptin/orphanin FQ receptor
  • Anxiety disorders such as generalized anxiety disorder, panic disorder with and without agoraphobia , post traumatic stress disorder, acute stress disorder, and phobias including social phobia/social anxiety, are the most common class of mental disorders in the general population and cause significant health and social problems.
  • Anxiety Disorders affect about 40 million American adults age 18 years and older (about 18%) in a given year, causing them to experience unreasonable levels of fearfulness and uncertainty. Worldwide, the estimated lifetime prevalence of any anxiety disorder is over 15%, while the 12-month prevalence is more than 10%.
  • SSRI antidepressants which inhibit the reuptake of serotonin, buspirone (5-HTIA partial agonist), and benzodiazepines, which increase chloride conductance through the GABA- A receptor and thus broadly inhibit neurotransmission.
  • SSRIs and buspirone while commonly used to treat anxiety disorders, often produce unwanted side effects such as nausea, dizziness, headaches, and sleep disturbances, which can exacerbate anxiety symptoms.
  • SSRI treatment is also prone to discontinuation syndrome upon cessation of treatment.
  • Benzodiazepines typically produce a rapid anxiolytic effect, but evidence of longer-term efficacy is lacking.
  • benzodiazepines can cause sedation and exacerbate depressive symptoms, which are highly comorbid with anxiety.
  • Other medications used to treat anxiety disorders including atypical antipsychotics, anticonvulsants, and some SSRIs also produce unwanted weight gain.
  • the Nociceptin/orphanin FQ receptor (NOC/OFQ), specifically the ORL-1 receptor, is a Class A G-protein coupled receptor (GPCR) that is expressed primarily in the central nervous system and peripheral nervous system as well as in the gastrointestinal tract, smooth muscle, and immune system. While related structurally to opioid receptors, the OFQ/Nociceptin system exhibits no significant cross reactivity to the classical opioid receptors mu, delta and kappa. Moreover, nociceptin exhibits anti-opioid activity in vivo (e.g. ORQ/Nociceptin, the natural ligand for ORL-1 receptor, has been reported to exhibit anti-nociceptive properties).
  • GPCR G-protein coupled receptor
  • Nociceptin/orphanin FQ receptor (NOC/OFQ) antagonists specifically antagonists of the ORL- 1 receptor, have demonstrated anti-depressant like activity and anorectic activity in several animal models for depression and feeding behavior.
  • ORL-1 antagonists are deemed to be useful in the treatment of depression and/or the treatment of overweight, obesity, and/or weight maintenance post treatment for overweight or obesity.
  • Other studies suggest possible use of antagonists in the treatment of pain, dementia and Parkinsonism.
  • Nociceptin/orphanin FQ receptor (NOC/OFQ) agonists have been implicated for the treatment of alcohol use disorders, anxiety, pain, stress induced anorexia, cough, neurogenic bladder, edema, and drug dependence, (see e.g. Murphy, Niall P. (2010), The Nociceptin/Orphanin FQ System as a Target for Treating Alcoholism. CNS & Neurological Disorders - Drug Tartgets 9:87-93.; and Chiou, L.C., Liao, Y.Y., Fan, P.C., Kuo, P.H., Wang, C. H., Riemer, C. and Prinssen, E.P. (2007), Nociceptin/Orphanin FQ Peptide Receptors:
  • WO 2011/060035 and WO 2011/060217 describe certain spiropiperidine compounds as ORL- 1 antagonists for use in the treatment of depression, overweight, obesity, weight maintenance and migraine.
  • the present invention provides a family of 4', 5'- dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran] compounds having potent antagonist activity at the ORL- 1 receptor, which are believed to be useful for the treatment of anxiety disorders, as for example generalized anxiety disorder, panic disorder, post traumatic stress disorder, acute stress disorder, or social phobia/social anxiety, or a combination thereof. More particularly, the present invention provides a compound of Formula I:
  • an anxiety disorder as for example, generalized anxiety disorder, panic disorder, post traumatic stress disorder, acute stress disorder, or social phobia/social anxiety, or a combination thereof;
  • R 1 is fluoro or chloro
  • R 2a and R 2b are each hydrogen or are each fluoro
  • R 3 is hydrogen, methyl, hydroxymethyl, or (C1-C3) alkoxymethyl
  • R 4 is selected from the group consisting of fluoro, chloro, cyano, cyanomethyl, (C1-C3) alkyl, cyclopropyl, hydroxymethyl, methoxy, cyclopropylmethoxy,
  • cyclopropylmethoxymethyl 1 -hydroxy- 1-methylethyl, aminocarbonyloxymethyl, methylaminocarbonyloxymethyl, dimethylaminocarbonyloxymethyl, aminocarbonyl, aminocarbonylmethyl, -CH 2 -NR 5 R 6 , hydroxyimine, methoxyimine, morpholin-4-yl, morpholin-4-ylmethyl, Ar 1 , tetrahydrofuran-2-yl, 3-oxomorpholin-4- ylmethyl, 2-oxopyrrolidin-l-ylmethyl, and 2-oxopiperidin-l-ylmethyl;
  • R 4 is selected from the group consisting of fluoro, chloro, cyano, cyanomethyl, (C1-C3) alkyl, cyclopropyl, hydroxymethyl, methoxy, methoxymethyl,
  • R 5 is hydrogen, C1-C3 alkyl, cyanomethyl, -C(0)CH 3 , or aminocarbonylmethyl;
  • R 5 is hydrogen, C1-C4 alkyl, cyclopropyl, hydroxyethyl, methoxyethyl, -C(0)CH 3 , or -C(0)0(C C 3 ) alkyl;
  • R 6 is hydrogen or methyl
  • R 7 is hydrogen, fluoro, chloro, methyl, hydroxymethyl, or methoxy
  • Ar 1 is a moiety selected from the group consisting of imidizol-l-yl, imidizol-2-yl,
  • Ar 2 is a moiety selected from the group consisting of imidizol-l-yl, imidizol-2-yl,
  • compositions for treating an anxiety disorder comprising a compound of Formula I or a
  • Another aspect of the present invention provides a method of treating an axiety disorder in a human, as for example, generalized anxiety disorder, panic disorder, post traumatic stress disorder, acute stress disorder, or social phobia/social anxiety, or a combination thereof, comprising administering to a human in need of such treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • Another aspect of this invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an anxiety disorder, as for example, generalized anxiety, panic disorder, post traumatic stress disorder, acute stress disorder, or social phobia/social anxiety, or a combination thereof.
  • an anxiety disorder as for example, generalized anxiety, panic disorder, post traumatic stress disorder, acute stress disorder, or social phobia/social anxiety, or a combination thereof.
  • the compounds for use in the present invention are bases, and accordingly react with a number of organic and inorganic acids to form pharmaceutically acceptable salts.
  • Use of pharmaceutically acceptable salts of each of the compounds of the present invention are contemplated within the scope of the present application.
  • pharmaceutically acceptable salt refers to any salt of a compound of Formula I that is substantially non-toxic to living organisms. Such pharmaceutically acceptable salts and common methodology for preparing them are well known in the art. See, e.g., P. Stahl, et al., HANDBOOK OF PHARMACEUTICAL SALTS:
  • the salt is a tartrate salt. In another embodiment the salt is a HC1 salt.
  • Preferred compounds for use in the present invention are compounds wherein:
  • R 1 is chloro
  • R 2a and R 2b are each fluoro
  • R 1 is chloro and R 2a and R 2b are each fluoro;
  • R 1 is fluoro and R 2a and R 2b are each hydrogen;
  • R 3 is hydrogen, methyl, hydroxymethyl, or methoxymethyl
  • R 3 is methyl
  • R 3 is hydroxymethyl
  • R 1 is chloro, R 2a and R 2b are each fluoro, and R 3 is methyl;
  • R 1 is chloro, R 2a and R 2b are each fluoro, and R 3 is hydroxymethyl;
  • R 4 is fluoro, hydroxymethyl, methoxymethyl, or pyrazol-l-ylmethyl
  • R 4 is methoxymethyl
  • R 4 is pyrazol-l-ylmethyl
  • R 7 is hydrogen, fluoro, or chloro
  • R 7 is fluoro
  • R 1 is chloro, R 2a and R 2b are each fluoro, and R 7 is fluoro;
  • R 1 is chloro, R 2a and R 2b are each fluoro, R 3 is methyl, and R 7 is fluoro;
  • R 1 is chloro, R 2a and R 2b are each fluoro, R 3 is hydroxymethyl, and R 7 is fluoro;
  • R 4 is fluoro, hydroxymethyl, methoxymethyl, methylcarbonyl or
  • R 4 is fluoro
  • R 4 is methylcarbonyl
  • R 4 is hydroxymethyl
  • R 4 is methoxymethyl
  • R 4 is methylcarbonyl; 34) any one of preferred embodiments 1) through 9) or 19) through 23) wherein R 4 is 2-methylimidazol-l-yl
  • Certain preferred compounds for use in the present invention are the compounds exemplified in the following table and their pharmaceutically acceptable salts:
  • R a and R are each fluoro are also preferred because certain of such compounds have a more favorable pharmacokinetic profile, being more stable to oxidative metabolism. This is thought to have the general effect of improving the oral bioavailability of the compounds.
  • the compounds for use in the present invention and methods of making them are known in the art and are characterized as potent and selective ORL-1 receptor antagonists. They can be prepared according to known synthetic schemes by methods well known and appreciated in the art. See for example WO 2011/060035 and WO 2011/060217.
  • ORL- 1 receptor antagonists are effective in rodent models of anxiety.
  • representative compounds may be run in the following in vivo assays:
  • Hyperthermia is a general phenomenon that has been reliably demonstrated in many species in response to stress, and is a component of the well-characterized fight-or- flight response (Pechnick RN and Morgan MJ. 1987. The role of endogenous opioids in footshock-induced hyperthermia. Pharmacol. Biochem. Behav. 28(1): 95-100.)
  • the conventional and minimally-invasive method for analyzing stress-induced hyperthermia is by measuring body temperature, and stress-induced increases in body temperature, with a rectal thermometer.
  • Male Fischer F-344 rats Hard, Indianapolis, IN, USA) weighing between 275 - 350 g are tested. All animals are individually-housed with food and automated water available ad libitum, and maintained on a 12 nr.
  • the mGlu5 antagonist MTEP (3-[(2-methyl-l,3-thiazol-4-yl)ethynyl]pyridine)(Brodkin J, Bradbury M, Busse C, Warren N, Bristow LJ, Varney MA., Reduced stress-induced hyperthermia in mGluR5 knockout mice, Eur J Neurosci.; 16(11):2241-4 (2002 Dec), which has demonstrated robust anxiolytic -like activity in preclinical models, is used as a positive control (10 mg/kg, p.o., dissolved in water). Immediately following dosing, rats are returned to their home cage, and the experimenter turns off the lights and leaves the room. The dosing room (Room A) is darkened for the remainder of the 60 min pretreatment period.
  • rats are taken individually to a brightly lit adjacent room (Room B) where baseline body temperatures are determined by insertion of a rectal probe lubricated with USP grade mineral oil.
  • Body temperature is assessed using a PHYSITEMP BAT-12 ® Microprobe Thermometer with a PHYSITEMP RET-2 ® rat rectal probe (Physitemp Instruments Inc., Clifton, NJ, USA).
  • the probe is inserted approximately 2 cm into the rectum, to measure the core body temperature (this is the baseline body temperature, Tl, in degrees Celcius).
  • T2 - Tl The difference in body temperature (T2 - Tl) is defined as the stress-induced hyperthermic response.
  • the dose at which a compound produces a 35% reduction in stress-induced hyperthermia, relative to the vehicle response is defined as the T35 dose, which also represents a response level that is of both statistical and physiological significance.
  • Representative compounds for use in the present invention are assayed essentially as described above and are found to reduce stress-induced hyperthermia compared to vehicle treated rats, without an effect on basal body temperature.
  • Exemplified Compounds 1, 2, 5, and 9 are assayed essentially as described above and are found to produce a dose-dependent reduction in stress-induced hyperthermia without affecting basal core body temperature (see Table 1). Based on these results, the compounds for use in the present invention may have anxiolytic activity in vivo.
  • T35 values are estimated from dose response curves generated independently for each compound.
  • conditioned fear stress-induced freezing behavior can be used as a model of anxiety (Fanselow MS and F.J. Helmstetter FJ. 1988. Conditional analgesia, defensive freezing, and benzodiazepines. Behav. Neurosci. 102: 233-243).
  • This freezing behavior is attenuated by both benzodiazepine and non- benzodiazepine anxiolytics. Therefore, this animal model may be useful for evaluating the potential efficacy of various therapeutic agents for anxiety disorders.
  • Conditioned fear is induced by pairing a neutral environmental stimulus
  • CS conditioned stimlus
  • US unconditioned stimulus
  • aversive outcome [unconditioned stimulus (US), e.g., electric footshock].
  • Re-exposure to the CS elicits a stereotypic, reproducible, and quantifiable behavioral response (conditioned response, e.g., immobility/freezing).
  • conditioned response e.g., immobility/freezing
  • the ability of compounds of the present invention to attenuate a conditioned fear response (immobility/freezing) to a stimulus previously paired with aversive foot-shock is assessed in C57B1/6 mice and compared to the effects of the positive control mGlu5 receptor antagonist MPEP.
  • mice receive one training session in which a neutral tone conditioned stimulus (CS: 5 kHz, 100 dB, 30 sec duration) is paired with a scrambled foot-shock unconditioned stimulus (0.57 mA, 2 sec duration, co- terminating).
  • CS neutral tone conditioned stimulus
  • mice Following a 60-min pretreatment period, mice are placed in a novel environment and allowed to explore for 2 min., during which time no stimuli are presented. Following the 2 min. pre-CS period, the tone CS is presented continuously for four minutes, in the absence of further shock presentation. The ability of the tone CS to elicit a conditioned fear response
  • immobility/freezing is used as a measure of anxiety or fear, where increased immobility indicates increased anxiety.
  • Representative compounds for use in the present invention are assayed essentially as described and are found to attenuate the immobility/freezing response to the tone CS compared to vehicle treated mice. No decrease in immobility during the pre-CS period is observed, indicating a lack of nonselective sedative-like effects.
  • Exemplified Compounds 1, 2, 9 and 10 are assayed essentially as described above and are found to significantly attenuate the immobility response to the tone CS compared to vehicle treated mice without a decrease in immobility during the pre-CS period (see Table 2). Based on these results, the compounds for use in the present invention may have anxiolytic activity in vivo.
  • mice Male CF-1 mice (18-20g) (Harlan Industries (Indianapolis, IN) are housed in an enriched environment in groups of 8 mice per 6" polycarbonate cage (Lab Products, 144.5 sq. in.) and maintained on Harlan Tech Lab Rodent Chow 2014 (Madison,
  • Alprazolam is used as a positive control (1 mg/kg in 10% ⁇ -cylcodextrin vehicle (BCD, Sigma), dosed IP 30 min. prior to stressor).
  • vehicle control 'no stress' mice are sacrificed without being subjected to a foot- shock.
  • Vehicle 'stress', test compound, and alprazolam treated mice are subjected to a stressor of inescapable electric footshock (1 mA intensity for 10 sec) in a metal cage with a stainless steel grid floor (Coulbourn Instruments, L.L.C. 7462 Penn Drive, Allentown, PA 18106).
  • the mice are then immediately sacrificed using a beam of microwave radiation focused on the skull for 0.5 sec (Thermax Thermatron, Louisville, KY).
  • the cerebellum is quickly removed from the skull, and the tissue placed in a polystyrene tube containing 2.0 ml 1% perchloric acid (PCA) on ice. Tissue samples are homogenized and incubated on ice for 30 min. The samples are then boiled for 5 min. The tubes are then centrifuged at ll,700xg for 20 min. at room temperature and 1.0 ml of supernatant is acetylated by adding 40 ⁇ of triethylamine and 20 ⁇ of acetic anhydride. The samples are immediately vortexed and then centrifuged at 13,000xg for 20 min. at 4°C.
  • PCA perchloric acid
  • the cGMP assay buffer includes the following: 0.05 M sodium acetate, trihydrate (6.8 g/L) and 0.1% sodium azide adjusted to pH 6.2 with acetic acid.
  • a separate tracer buffer is prepared for the radioligand tracer using cGMP assay buffer containing 2 mM EDTA disodium salt dihydrate (0.7 g/L), and 1% normal rabbit serum (Perkin Elmer, FP526).
  • 125 I-cGMP (guanosine 3 ',5 '-cyclic phosphoric acid 2'-0- succinyl[ 125 IJiodotyrosine methyl ester, Perkin Elmer, SA 2200 Ci/mmol, 32.3 uCi/ml, NEX-131, Boston, MA), is prepared in tracer buffer at a concentration of 0.75 ⁇ /10 ml and added to each well of a FlashPlateTM (Perkin Elmer Life Sciences, Boston, MA, SMP002). A cGMP standard curve is prepared using guanosine-3' :5'-cyclic
  • monophosphate lyophilized standard Perkin Elmer, FP523 reconstituted with 2.0 ml of distilled water to make a 2000 pm/ml solution (stored @ 4°C) that is diluted with assay buffer to generate a 9-point standard curve.
  • a 1.0 ml aliquot of each standard, including a blank, is acetylated by adding 40 ⁇ triethylamine and 20 ⁇ acetic anhydride, vortexed and incubated for 3 min. prior to plate addition. 100 ⁇ of each standard is added, in duplicate, to FlashPlateTM wells, including two 100 ⁇ aliquots directly from the stock cGMP standard bottle for nonspecific binding (NSB) determination.
  • NBS nonspecific binding
  • cGMP data calculations are performed using Excel and GraphPad Prism. Mean counts per minute (cpms) from duplicate samples are calculated and the average NSB cpms subtracted to generate specific cpms. Specific cpms are used to determine the Normalized % Bound. GraphPad Prism is used to determine the nonlinear regression curve fit from the Normalized % Bound for the standard curve and interpolate the values of the unknown samples as log pmol cGMP. Results are normalized to tissue weights for each sample to calculate pmol cGMP/gram tissue. Group averages are calculated as % Vehicle Control and % Vehicle Stress Control and the SEM is determined.
  • compounds for use in the present invention may be useful in the treatment of patients with anxiety disorders, as for example, generalized anxiety, panic disorder, post traumatic stress disorder, acute stress disorder, or social phobia/social anxiety, or a combination thereof.
  • compositions comprising at least one compound of Formula I, or a pharmaceutically acceptable salt thereof, as an active ingredient and at least one pharmaceutically acceptable carrier, diluent and/or excipient.
  • These compositions can be administered by a variety of routes including oral, intranasal, transdermal, subcutaneous, intravenous, intramuscular, and pulmonary.
  • Such pharmaceutical compositions and processes for preparing them are well known in the art. See, e.g. , Remington: The Science and Practice of Pharmacy (University of the Sciences in Philadelphia, ed., 21 st ed., Lippincott Williams & Wilkins Co., 2005).
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.1 to about 500 mg, more usually about 1.0 to about 200 mg, as for example between about 5 and 50 mg of the active ingredient.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with at least one suitable pharmaceutically acceptable carrier, diluent and/or excipient.
  • the compounds of Formula I are generally effective over a wide dosage range.
  • dosages per day normally fall within the range of about 0.01 to about 50 mg/kg, more usually from about 0.05 to 5.0 mg/kg, and as for example between 0.1 and 1.0 mg/kg of body weight.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, and therefore the above dosage range is not intended to limit the scope of the invention in any way.
  • the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.

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Abstract

L'invention concerne l'utilisation des antagonistes du récepteur ORL-1 de formule (I) pour le traitement de troubles de l'anxiété.
PCT/US2013/051575 2012-07-31 2013-07-23 Antagoniste du récepteur orl-1 pour le traitement de l'anxiété WO2014022143A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1873150A1 (fr) * 2006-06-30 2008-01-02 Nikem Research S.R.L. Indoleamides fluores utiles comme ligands du recepteur ORL-1
WO2011060035A1 (fr) 2009-11-16 2011-05-19 Eli Lilly And Company Composés de spiropipéridine en tant qu'antagonistes de récepteur orl-1
WO2011060217A1 (fr) 2009-11-16 2011-05-19 Eli Lilly And Company Composés de spiropipéridine en tant qu'antagonistes de récepteur orl-1

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1873150A1 (fr) * 2006-06-30 2008-01-02 Nikem Research S.R.L. Indoleamides fluores utiles comme ligands du recepteur ORL-1
WO2011060035A1 (fr) 2009-11-16 2011-05-19 Eli Lilly And Company Composés de spiropipéridine en tant qu'antagonistes de récepteur orl-1
WO2011060217A1 (fr) 2009-11-16 2011-05-19 Eli Lilly And Company Composés de spiropipéridine en tant qu'antagonistes de récepteur orl-1

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"Remington: The Science and Practice of Pharmacy", 2005, LIPPINCOTT WILLIAMS & WILKINS CO.
BRODKIN J; BRADBURY M; BUSSE C; WARREN N; BRISTOW LJ; VARNEY MA.: "Reduced stress-induced hyperthermia in mGluR5 knockout mice", EUR J NEUROSCI., vol. 16, no. 11, December 2002 (2002-12-01), pages 2241 - 4
CHIOU, L.C.; LIAO, Y.Y.; FAN, P.C.; KUO, P.H.; WANG, C. H.; RIEMER, C.; PRINSSEN, E.P.: "Nociceptin/Orphanin FQ Peptide Receptors: Pharmacology and Clinical Implications", CURRENT DRUG TARGETS, vol. 8, 2007, pages 117 - 135
FANSELOW MS; HELMSTETTER FJ.: "Conditional analgesia, defensive freezing, and benzodiazepines", BEHAV. NEUROSCI., vol. 102, 1988, pages 233 - 243
MARCELO DUZZIONI ET AL: "Anxiolytic-like effect of central administration of NOP receptor antagonist UFP-101 in rats submitted to the elevated T-maze", BEHAVIOURAL BRAIN RESEARCH, ELSEVIER, AMSTERDAM, NL, vol. 222, no. 1, 24 March 2011 (2011-03-24), pages 206 - 211, XP028378945, ISSN: 0166-4328, [retrieved on 20110331], DOI: 10.1016/J.BBR.2011.03.056 *
MURPHY, NIALL P.: "The Nociceptin/Orphanin FQ System as a Target for Treating Alcoholism", CNS & NEUROLOGICAL DISORDERS - DRUG TARTGETS, vol. 9, 2010, pages 87 - 93
P. STAHL ET AL.: "HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE", 2008, VCHA/WILEY-VCH
PECHNICK RN; MORGAN MJ: "The role of endogenous opioids in footshock-induced hyperthermia", PHARMACOL. BIOCHEM. BEHAV., vol. 28, no. 1, 1987, pages 95 - 100
S.M. BERGE ET AL.: "Pharmaceutical Salts", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 66, no. 1, January 1977 (1977-01-01)

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