Antalarmin

Antalarmin
Clinical data
Other namesAntalarmin
ATC code
  • none
Legal status
Legal status
  • In general: legal
Identifiers
IUPAC name
  • N-butyl-N-ethyl-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidin-4-amine
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC24H34N4
Molar mass378.564 g·mol−1
3D model (JSmol)
SMILES
  • n1c2c(c(nc1C)N(CC)CCCC)c(c(n2c3c(cc(cc3C)C)C)C)C
InChI
  • InChI=1S/C24H34N4/c1-9-11-12-27(10-2)23-21-18(6)19(7)28(24(21)26-20(8)25-23)22-16(4)13-15(3)14-17(22)5/h13-14H,9-12H2,1-8H3 checkY
  • Key:IXPROWGEHNVJOY-UHFFFAOYSA-N checkY
  (verify)

Antalarmin (CP-156,181) is a drug that acts as a CRH1 antagonist.

Corticotropin-releasing hormone (CRH), also known as Corticotropin-releasing factor, is an endogenous peptide hormone released in response to various triggers such as chronic stress and drug addiction. Such triggers result in the release of corticotropin (ACTH), another hormone involved in the physiological response to stress. Chronic release of CRH and ACTH is believed to be directly or indirectly involved in many of the harmful physiological effects of chronic stress, such as excessive glucocorticoid release, stomach ulcers, anxiety, diabetes mellitus, osteoporosis, depression, and development of high blood pressure and consequent cardiovascular problems.[1]

Antalarmin is a non-peptide drug that blocks the CRH1 receptor, and, as a consequence, reduces the release of ACTH in response to chronic stress.[2] This has been demonstrated in animals to reduce the behavioral responses to stressful situations,[3] and it is proposed that Antalarmin itself, or more likely newer CRH1 antagonist drugs still under development,[4] could be useful for reducing the adverse health consequences of chronic stress in humans, as well as having possible uses in the treatment of conditions such as anxiety, depression, and drug addiction.[5]

Chemical Structure

The synthesis of CP-154,526, a non-peptide antagonist of the CRH1 receptor, was first described in 1997.[6] Antalarmin, or CP-156,181, is a close analog that is highly structurally similar and has been shown to be easier to synthesize.[2] The findings from several chemical, pharmacokinetic and pharmacological studies indicate that the two compounds possess very similar in their properties.

Chemical structure of CRH1 receptor Non-peptide Antagonist CP-154,526 and its close analog, Antalarmin (CP-156,181)

Mechanism of Action

Receptor Binding

As shown in Table 1, Adenylyl cyclase and cAMP assays were used in various functional studies to determine the amount of cAMP inhibition by two CRH1 receptor antagonists: Antalarmin and CP-154,526.

Functional Data for Antalarmin (CP-156,181) and CP-154,526
Tissue Type of Assay Compound Parameter
Human SH-SY5Y (Neuroblastoma) cAMP Antalarmin pKb = 9.19 [7]
Human Y79 Cells (Retinoblastoma) cAMP Antalarmin IC50 = 0.8 nM [8]
Human SH-SY5Y cAMP CP-154,526 pKb = 7.76 [7]
Rat Cortex Cyclase CP-154,526 Ki = 3.7 nM [9]

Several receptor binding studies have shown that Antalarmin and CP-154,526 have high affinity for CRH1 receptors, with very similar profiles. Table 2 shows the binding affinities of each compound in various cell lines.

CRH1 receptor binding affinity for Antalarmin and CP-154,526
Tissue Compound Ki (nM) IC50 (nM)
Rat Pituitary Antalarmin 1.9 [2] 0.04 [10]
Rat Frontal Cortex Antalarmin 1.4 [2]
Human Clone Antalarmin 6 [8] 5 [10]
Rat Pituitary CP-154,526 1.4 [9]
Rat Cortex CP-154,526 5.7 [9]
Human Clone CP-154,526 10 [11]

Pharmacokinetics (ADME)

The pharmacokinetics of CP-154,526, a close analog of Antalarmin, have been investigated in male Sprauge-Dawley rats via intravenous (i.v.) and oral (p.o.) routes.[12] Following a 5 mg/kg dose (i.v.) of CP-154,526, drug concentrations followed a biphasic decline over time. CP-154,526 also demonstrated a large volume of distribution (Vd) at 6.7 L/kg, indicating extensive binding of the drug to tissue in Sprauge-Dawley rats. A plasma clearance of 82 ml/min/kg was observed with an estimated elimination half-life of 1.5 hours. Following p.o. administration at a dose of 10 mg/kg, an average peak plasma concentration (Cmax) of 367 ng/mL was determined within 0.5-1 hour of administration. The oral bioavailability was calculated to be 37%, resulting in an estimated hepatic clearance of 63%.[12]

In male Wistar rats given a 5 mg/kg dose (p.o) of CP-154,526, an oral bioavailability of 27% and high volume of distribution at 105 L/kg was determined, with an estimated total clearance (CLt) of 36 ml/min/kg. CP-154,526 was also observed to cross the blood-brain barrier with good penetrance at a 2.5 brain:plasma ratio 8 hours following oral administration.[13] An extensive pharmacokinetic study of Antalarmin conducted in macaques reported an oral bioavailability of 19%, a total clearance of 4.5 L/hr/kg, and an elimination half-life of 7.8 hours following a 20 mg/kg administration (p.o.). This same dose also resulted in mean Antalarmin plasma levels of 76 ng/ml and CSF levels of 9.8 ng/ml at 3 hours post-administration.[14]

In vitro and In vivo Research

Results so far have had limited success, with various CRF antagonists being tested, which showed some antidepressant effects, but failed to produce an effect comparable with conventional antidepressant drugs.[15] However more positive results were seen when Antalarmin was combined with an SSRI antidepressant, suggesting a potential for synergistic effect.[16] Encouraging results have also been observed using Antalarmin as a potential treatment for anxiety[17][18] and stress-induced hypertension.[19]

Initial studies investigating CP-154,526 showed that the compound binds with high affinity to cortical and pituitary CRH receptors across several species. Additionally, systemic administration of CP-154,526 fully antagonizes the effects of exogenous CRH on ACTH levels, cell firing in the locus coeruleus, and fear potentiation in animal models.[9] However, this potent and selective compound demonstrated low oral bioavailability, and in vitro studies using human liver microsomes predicted high hepatic clearance, deeming the compound unsuitable for clinical development. Nevertheless, many investigators continue to study CP-154,526 and its close analogs (e.g. Antalarmin), using them as tools to examine the physiology of CRH and CRH receptors, as well as to determine the potential therapeutic value of CRH1 antagonists in several CNS and peripheral disorders.[20]

Stress and Anxiety

In vitro studies examining the effects of CRH1 antagonists on the Hypothalmic-Pituitary-Adrenal (HPA) axis showed that Antalarmin inhibited ACTH release in rat anterior pituitary cells,[21] as well as inhibited cortisol synthesis and release in human adrenal cells.[22] In vivo studies revealed that pre-treating rats with Antalarmin inhibited increases in plasma ACTH following CRH injection (i.v.), with no effect on baseline levels.[2] However, another study demonstrated that 8 weeks of Antalarmin administered twice daily (i.p.) in rats significantly lowered basal ACTH and corticosterone levels, resulting in reduced adrenocortical responsiveness to ACTH.[23] When Antalarmin was administered to primates, it also inhibited increases in plasma ACTH, as well as prevented the anxiety response produced by a social stressor (e.g. presentation of another male in an unfamiliar environment).[14]

With regards to neurochemical effects, Antalarmin has been shown to inhibit increases in extracellular cortical norepinephrine induced by rat tail pinch,[24] suggesting that CHR1 receptors may be implicated in stress-evoked norepinephrine release in the cortex. Antalarmin was also shown to have electrophysiological effects by partially reversing the inhibition of neuronal firing in the dorsal raphe nucleus that occurs following intracerebroventricular (i.c.v) administration of CRH.[25]

Studies using CRH receptor antagonists such as Antalarmin in anxiety models have shown that these agents produce effects similar to clinically effective anxiolytics.[26][27] In conditioned fear models, Antalarmin reduced conditioned freezing behavior, suggesting that it blocked the development and expression of conditioned fear, and implicating CRH1 receptors in both processes.[28] Oral administration of Antalarmin (3–30 mg/kg) also significantly reduced immobility in a rat model of behavioral despair, with effects similar to the SSRI fluoxetine.[26][29]

Neurodegeneration

CRH has also been shown to promote neurodegeneration, suggesting that CRH1 antagonists may have neuroprotective effects. PC12 cells are derived from the rat adrenal medulla and are extensively used to study neural differentiation. PC12 cells treated with CRH (1-10 nM) showed increased numbers of apoptotic cells and upregulation of the Fas ligand via p38 activation, demonstrating the pro-apoptotic effects of CRH. Administration of Antalarmin (10 nM) completely blocked the CRH-induced apoptosis response and inhibited Fas ligand expression.[30]

Inflammation

Antalarmin has also been used extensively to study the role of CRH in inflammation. Intraperitoneal (i.p.) administration of Antalarmin in rats significantly inhibited the inflammation caused by subcutaneous administration of carrageenan (a known inflammatory food additive) as measured by leukocyte concentrations.[2] In a rat skin mast cell activation model, pre-treatment with Antalarmin (10 mg/kg, i.v.) inhibited the CRH-stimulated induction of mast cell degranulation,[31] suggesting pro-inflammatory properties of CRH. Antalarmin also blocked the vascular permeability and mast cell degranulation response induced by intradermal Urocortin (10 nM).[31] Collectively, these results indicate that during stress, CRH leads to the activation of skin mast cells through the CRH1 receptor which triggers vasodilation and increased vascular permeability.

Chronic Antalarmin treatment also showed anti-inflammatory effects and has been suggested as having potential uses in the treatment of inflammatory conditions such as arthritis,[32] as well as stress-induced gastrointestinal ulcers[33] and irritable bowel syndrome.[34][35]

Addiction

Mixed results have been seen in research into the use of Antalarmin and other CRF-1 antagonists in the treatment of drug addiction disorders. Tests of Antalarmin on cocaine use in cocaine-addicted monkeys produced only slight reductions of use that were not statistically significant,[36] however in tests on cocaine-addicted rats, Antalarmin did prevent dose escalation with prolonged use, suggesting that it might stabilize cocaine use and prevent it increasing over time, although without consistently reducing it.[37]

Antalarmin also showed positive effects in reducing withdrawal syndrome from chronic opioid use,[38] and significantly reduced self-administration of ethanol in ethanol-addicted rodents.[39][40][41]

Overall, additional research is needed to determine the therapeutic efficacy of Antalarmin and other CRH non-peptide antagonists in anxiety, depression, inflammation, neurodegenerative disease, and addiction.[20]

See also

References

  1. ↑ Zoumakis E, Rice KC, Gold PW, Chrousos GP (November 2006). "Potential uses of corticotropin-releasing hormone antagonists". Annals of the New York Academy of Sciences. 1083 (1): 239–51. Bibcode:2006NYASA1083..239Z. doi:10.1196/annals.1367.021. PMID 17148743. S2CID 7731338.
  2. 1 2 3 4 5 6 Webster EL, Lewis DB, Torpy DJ, Zachman EK, Rice KC, Chrousos GP (December 1996). "In vivo and in vitro characterization of antalarmin, a nonpeptide corticotropin-releasing hormone (CRH) receptor antagonist: suppression of pituitary ACTH release and peripheral inflammation". Endocrinology. 137 (12): 5747–50. doi:10.1210/endo.137.12.8940412. PMID 8940412.
  3. ↑ Deak T, Nguyen KT, Ehrlich AL, Watkins LR, Spencer RL, Maier SF, et al. (January 1999). "The impact of the nonpeptide corticotropin-releasing hormone antagonist antalarmin on behavioral and endocrine responses to stress". Endocrinology. 140 (1): 79–86. doi:10.1210/endo.140.1.6415. PMID 9886810.
  4. ↑ Nielsen DM, Carey GJ, Gold LH (September 2004). "Antidepressant-like activity of corticotropin-releasing factor type-1 receptor antagonists in mice". European Journal of Pharmacology. 499 (1–2): 135–46. doi:10.1016/j.ejphar.2004.07.091. PMID 15363960.
  5. ↑ McCarthy JR, Heinrichs SC, Grigoriadis DE (May 1999). "Recent advances with the CRF1 receptor: design of small molecule inhibitors, receptor subtypes and clinical indications". Current Pharmaceutical Design. 5 (5): 289–315. PMID 10213797.
  6. ↑ Chen YL, Mansbach RS, Winter SM, Brooks E, Collins J, Corman ML, et al. (May 1997). "Synthesis and oral efficacy of a 4-(butylethylamino)pyrrolo[2,3-d]pyrimidine: a centrally active corticotropin-releasing factor1 receptor antagonist". Journal of Medicinal Chemistry. 40 (11): 1749–54. doi:10.1021/jm960861b. PMID 9171885.
  7. 1 2 Schoeffter P, Feuerbach D, Bobirnac I, Gazi L, Longato R (1999). "Functional, endogenously expressed corticotropin-releasing factor receptor type 1 (CRF1) and CRF1 receptor mRNA expression in human neuroblastoma SH-SY5Y cells". Fundamental & Clinical Pharmacology. 13 (4): 484–9. doi:10.1111/j.1472-8206.1999.tb00007.x. PMID 10456290. S2CID 31280442.
  8. 1 2 Gully D, Geslin M, Serva L, Fontaine E, Roger P, Lair C, et al. (April 2002). "4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A): a potent and selective corticotrophin-releasing factor(1) receptor antagonist. I. Biochemical and pharmacological characterization". The Journal of Pharmacology and Experimental Therapeutics. 301 (1): 322–32. doi:10.1124/jpet.301.1.322. PMID 11907190.
  9. 1 2 3 4 Schulz DW, Mansbach RS, Sprouse J, Braselton JP, Collins J, Corman M, et al. (September 1996). "CP-154,526: a potent and selective nonpeptide antagonist of corticotropin releasing factor receptors". Proceedings of the National Academy of Sciences of the United States of America. 93 (19): 10477–82. Bibcode:1996PNAS...9310477S. doi:10.1073/pnas.93.19.10477. PMC 38410. PMID 8816826.
  10. 1 2 Lundkvist J, Chai Z, Teheranian R, Hasanvan H, Bartfai T, Jenck F, et al. (August 1996). "A non peptidic corticotropin releasing factor receptor antagonist attenuates fever and exhibits anxiolytic-like activity". European Journal of Pharmacology. 309 (2): 195–200. doi:10.1016/0014-2999(96)00337-8. PMID 8874139.
  11. ↑ Gottowik J, Goetschy V, Henriot S, Kitas E, Fluhman B, Clerc RG, et al. (October 1997). "Labelling of CRF1 and CRF2 receptors using the novel radioligand, [3H]-urocortin". Neuropharmacology. 36 (10): 1439–46. doi:10.1016/S0028-3908(97)00098-1. PMID 9423932. S2CID 6235036.
  12. 1 2 Chen YL, Mansbach RS, Winter SM, Brooks E, Collins J, Corman ML, et al. (May 1997). "Synthesis and oral efficacy of a 4-(butylethylamino)pyrrolo[2,3-d]pyrimidine: a centrally active corticotropin-releasing factor1 receptor antagonist". Journal of Medicinal Chemistry. 40 (11): 1749–54. doi:10.1021/jm960861b. PMID 9171885.
  13. ↑ Keller C, Bruelisauer A, Lemaire M, Enz A (February 2002). "Brain pharmacokinetics of a nonpeptidic corticotropin-releasing factor receptor antagonist". Drug Metabolism and Disposition. 30 (2): 173–6. doi:10.1124/dmd.30.2.173. PMID 11792687.
  14. 1 2 Habib KE, Weld KP, Rice KC, Pushkas J, Champoux M, Listwak S, et al. (May 2000). "Oral administration of a corticotropin-releasing hormone receptor antagonist significantly attenuates behavioral, neuroendocrine, and autonomic responses to stress in primates". Proceedings of the National Academy of Sciences of the United States of America. 97 (11): 6079–84. Bibcode:2000PNAS...97.6079H. doi:10.1073/pnas.97.11.6079. PMC 18561. PMID 10823952.
  15. ↑ Jutkiewicz EM, Wood SK, Houshyar H, Hsin LW, Rice KC, Woods JH (July 2005). "The effects of CRF antagonists, antalarmin, CP154,526, LWH234, and R121919, in the forced swim test and on swim-induced increases in adrenocorticotropin in rats". Psychopharmacology. 180 (2): 215–23. doi:10.1007/s00213-005-2164-z. PMC 1315297. PMID 15696320.
  16. ↑ Ducottet C, Griebel G, Belzung C (June 2003). "Effects of the selective nonpeptide corticotropin-releasing factor receptor 1 antagonist antalarmin in the chronic mild stress model of depression in mice". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 27 (4): 625–31. doi:10.1016/S0278-5846(03)00051-4. PMID 12787849. S2CID 32290500.
  17. ↑ Zorrilla EP, Valdez GR, Nozulak J, Koob GF, Markou A (October 2002). "Effects of antalarmin, a CRF type 1 receptor antagonist, on anxiety-like behavior and motor activation in the rat". Brain Research. 952 (2): 188–99. doi:10.1016/S0006-8993(02)03189-X. PMID 12376179. S2CID 6797766.
  18. ↑ Habib KE, Weld KP, Rice KC, Pushkas J, Champoux M, Listwak S, et al. (May 2000). "Oral administration of a corticotropin-releasing hormone receptor antagonist significantly attenuates behavioral, neuroendocrine, and autonomic responses to stress in primates". Proceedings of the National Academy of Sciences of the United States of America. 97 (11): 6079–84. Bibcode:2000PNAS...97.6079H. doi:10.1073/pnas.97.11.6079. PMC 18561. PMID 10823952.
  19. ↑ Briscoe RJ, Cabrera CL, Baird TJ, Rice KC, Woods JH (October 2000). "Antalarmin blockade of corticotropin releasing hormone-induced hypertension in rats". Brain Research. 881 (2): 204–7. doi:10.1016/S0006-8993(00)02742-6. PMID 11036160. S2CID 12152273.
  20. 1 2 Seymour PA, Schmidt AW, Schulz DW (2003). "The pharmacology of CP-154,526, a non-peptide antagonist of the CRH1 receptor: a review". CNS Drug Reviews. 9 (1): 57–96. doi:10.1111/j.1527-3458.2003.tb00244.x. PMC 6741649. PMID 12595912.
  21. ↑ McCarthy JR, Heinrichs SC, Grigoriadis DE (May 1999). "Recent advances with the CRF1 receptor: design of small molecule inhibitors, receptor subtypes and clinical indications". Current Pharmaceutical Design. 5 (5): 289–315. PMID 10213797.
  22. ↑ Willenberg HS, Bornstein SR, Hiroi N, Päth G, Goretzki PE, Scherbaum WA, Chrousos GP (March 2000). "Effects of a novel corticotropin-releasing-hormone receptor type I antagonist on human adrenal function". Molecular Psychiatry. 5 (2): 137–41. doi:10.1038/sj.mp.4000720. PMID 10822340.
  23. ↑ Wong ML, Webster EL, Spokes H, Phu P, Ehrhart-Bornstein M, Bornstein S, et al. (1999). "Chronic administration of the non-peptide CRH type 1 receptor antagonist antalarmin does not blunt hypothalamic-pituitary-adrenal axis responses to acute immobilization stress". Life Sciences. 65 (4): PL53-8. doi:10.1016/s0024-3205(99)00268-4. PMID 10421433.
  24. ↑ Griebel G, Simiand J, Steinberg R, Jung M, Gully D, Roger P, et al. (April 2002). "4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1, 3-thiazol-2-amine hydrochloride (SSR125543A), a potent and selective corticotrophin-releasing factor(1) receptor antagonist. II. Characterization in rodent models of stress-related disorders". The Journal of Pharmacology and Experimental Therapeutics. 301 (1): 333–45. doi:10.1124/jpet.301.1.333. PMID 11907191.
  25. ↑ Kirby LG, Rice KC, Valentino RJ (February 2000). "Effects of corticotropin-releasing factor on neuronal activity in the serotonergic dorsal raphe nucleus". Neuropsychopharmacology. 22 (2): 148–62. doi:10.1016/S0893-133X(99)00093-7. PMID 10649828.
  26. 1 2 Griebel G (April 1999). "Is there a future for neuropeptide receptor ligands in the treatment of anxiety disorders?". Pharmacology & Therapeutics. 82 (1): 1–61. doi:10.1016/S0163-7258(98)00041-2. PMID 10341356.
  27. ↑ Britton KT, Lee G, Vale W, Rivier J, Koob GF (March 1986). "Corticotropin releasing factor (CRF) receptor antagonist blocks activating and 'anxiogenic' actions of CRF in the rat". Brain Research. 369 (1–2): 303–6. doi:10.1016/0006-8993(86)90539-1. PMID 3008937. S2CID 6290497.
  28. ↑ Deak T, Nguyen KT, Ehrlich AL, Watkins LR, Spencer RL, Maier SF, et al. (January 1999). "The impact of the nonpeptide corticotropin-releasing hormone antagonist antalarmin on behavioral and endocrine responses to stress". Endocrinology. 140 (1): 79–86. doi:10.1210/endo.140.1.6415. PMID 9886810.
  29. ↑ Porsolt RD, Bertin A, Jalfre M (October 1977). "Behavioral despair in mice: a primary screening test for antidepressants". Archives Internationales de Pharmacodynamie et de Therapie. 229 (2): 327–36. PMID 596982.
  30. ↑ Dermitzaki E, Tsatsanis C, Gravanis A, Margioris AN (April 2002). "Corticotropin-releasing hormone induces Fas ligand production and apoptosis in PC12 cells via activation of p38 mitogen-activated protein kinase". The Journal of Biological Chemistry. 277 (14): 12280–7. doi:10.1074/jbc.M111236200. PMID 11790788.
  31. 1 2 Theoharides TC, Singh LK, Boucher W, Pang X, Letourneau R, Webster E, Chrousos G (January 1998). "Corticotropin-releasing hormone induces skin mast cell degranulation and increased vascular permeability, a possible explanation for its proinflammatory effects". Endocrinology. 139 (1): 403–13. doi:10.1210/endo.139.1.5660. PMID 9421440.
  32. ↑ Webster EL, Barrientos RM, Contoreggi C, Isaac MG, Ligier S, Gabry KE, et al. (June 2002). "Corticotropin releasing hormone (CRH) antagonist attenuates adjuvant induced arthritis: role of CRH in peripheral inflammation". The Journal of Rheumatology. 29 (6): 1252–61. PMID 12064844.
  33. ↑ Gabry KE, Chrousos GP, Rice KC, Mostafa RM, Sternberg E, Negrao AB, et al. (2002). "Marked suppression of gastric ulcerogenesis and intestinal responses to stress by a novel class of drugs". Molecular Psychiatry. 7 (5): 474–83, 433. doi:10.1038/sj.mp.4001031. PMID 12082565.
  34. ↑ Greenwood-Van Meerveld B, Johnson AC, Cochrane S, Schulkin J, Myers DA (June 2005). "Corticotropin-releasing factor 1 receptor-mediated mechanisms inhibit colonic hypersensitivity in rats". Neurogastroenterology and Motility. 17 (3): 415–22. doi:10.1111/j.1365-2982.2005.00648.x. PMID 15916629. S2CID 25379651.
  35. ↑ Martinez V, Taché Y (2006). "CRF1 receptors as a therapeutic target for irritable bowel syndrome". Current Pharmaceutical Design. 12 (31): 4071–88. doi:10.2174/138161206778743637. PMID 17100612.
  36. ↑ Mello NK, Negus SS, Rice KC, Mendelson JH (December 2006). "Effects of the CRF1 antagonist antalarmin on cocaine self-administration and discrimination in rhesus monkeys". Pharmacology, Biochemistry, and Behavior. 85 (4): 744–51. doi:10.1016/j.pbb.2006.11.008. PMID 17182090. S2CID 8186943.
  37. ↑ Specio SE, Wee S, O'Dell LE, Boutrel B, Zorrilla EP, Koob GF (February 2008). "CRF(1) receptor antagonists attenuate escalated cocaine self-administration in rats". Psychopharmacology. 196 (3): 473–82. doi:10.1007/s00213-007-0983-9. PMC 2769571. PMID 17965976.
  38. ↑ Stinus L, Cador M, Zorrilla EP, Koob GF (January 2005). "Buprenorphine and a CRF1 antagonist block the acquisition of opiate withdrawal-induced conditioned place aversion in rats". Neuropsychopharmacology. 30 (1): 90–8. doi:10.1038/sj.npp.1300487. PMID 15138444.
  39. ↑ Funk CK, Zorrilla EP, Lee MJ, Rice KC, Koob GF (January 2007). "Corticotropin-releasing factor 1 antagonists selectively reduce ethanol self-administration in ethanol-dependent rats". Biological Psychiatry. 61 (1): 78–86. doi:10.1016/j.biopsych.2006.03.063. PMC 2741496. PMID 16876134.
  40. ↑ Chu K, Koob GF, Cole M, Zorrilla EP, Roberts AJ (April 2007). "Dependence-induced increases in ethanol self-administration in mice are blocked by the CRF1 receptor antagonist antalarmin and by CRF1 receptor knockout". Pharmacology, Biochemistry, and Behavior. 86 (4): 813–21. doi:10.1016/j.pbb.2007.03.009. PMC 2170886. PMID 17482248.
  41. ↑ Marinelli PW, Funk D, Juzytsch W, Harding S, Rice KC, Shaham Y, Lê AD (December 2007). "The CRF1 receptor antagonist antalarmin attenuates yohimbine-induced increases in operant alcohol self-administration and reinstatement of alcohol seeking in rats". Psychopharmacology. 195 (3): 345–55. doi:10.1007/s00213-007-0905-x. PMID 17705061. S2CID 25629995.
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