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Buprenorphine/samidorphan

January 01, 1970

Buprenorphine/samidorphan (developmental code name ALKS-5461) is a combination formulation of buprenorphine and samidorphan which is under development as an add on to antidepressants in treatment-resistant depression (TRD).[2]

Buprenorphine/samidorphan
Buprenorphine (top) + samidorphan (bottom)
Combination of
BuprenorphineOpioid modulator
SamidorphanOpioid antagonist
Clinical data
Other namesALKS-5461
Routes of
administration		Sublingual[1]
Legal status
Legal status
Identifiers
CAS Number
  • 2415438-51-4

ALKS-5461 failed to meet its primary efficacy endpoints in two trials from 2016.[3] On the basis of a third study that did meet its primary endpoints, Alkermes initiated a rolling New Drug Application with the FDA.[4]

In November 2018, an FDA panel voted against recommending approval, finding that evidence was insufficient.[5] As such, approval of the medication was rejected in 2019.[6] It is a κ-opioid receptor (KOR) antagonist and is being developed by Alkermes.

Pharmacology edit

See also: Buprenorphine § Pharmacology, and Samidorphan § Pharmacology

Pharmacodynamics edit

ALKS-5461 is a (1:1 ratio) combination of: (1) buprenorphine, a weak partial agonist of the μ-opioid receptor (MOR), antagonist/very weak partial agonist of the κ-opioid receptor (KOR), and, to a lesser extent, antagonist of the δ-opioid receptor (DOR) and weak partial agonist of the nociceptin receptor (NOP);[7][8][9][10] and (2) samidorphan, a preferential antagonist of the MOR (but also, to a slightly lesser extent, weak partial agonist of the KOR and DOR).[11][12][13][14] The combination of these two drugs putatively results in what is functionally a blockade of KORs with negligible activation of MORs.[9][12]

κ-Opioid receptor antagonism edit

It has been known since the 1980s that buprenorphine binds to at high affinity and antagonizes the KOR.[15][16]

Through activation of the KOR, dynorphins, opioid peptides that are the endogenous ligands of the KOR and that can, in many regards, be figuratively thought of as functional inverses of the morphine-like, euphoric and stress-inhibiting endorphins,[17] induce dysphoria and stress-like responses in both animals and humans,[18] as well as psychotomimetic effects in humans,[19][20] and are thought to be essential for the mediation of the dysphoric aspects of stress.[21] In addition, dynorphins are believed to be critically involved in producing the changes in neuroplasticity evoked by chronic stress that lead to the development of depressive and anxiety disorders, increased drug-seeking behavior, and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis.[17][21][22] In support of this, in knockout mice lacking the genes encoding the KOR and/or prodynorphin (the endogenous precursor of the dynorphins), many of the usual effects of exposure to chronic stress are completely absent, such as increased immobility in the forced swimming test (a widely employed assay of depressive-like behavior) and increased conditioned place preference for cocaine (a measure of the rewarding properties and addictive susceptibility to cocaine).[23] Accordingly, KOR antagonists show robust efficacy in animal models of depression, anxiety, anhedonia, drug addiction, and other stress-related behavioral and physiological abnormalities.[17][18][24][25]

A mouse study found that knockout of the MOR or DOR or selective pharmacological ablation of the NOP did not affect the antidepressant-like effects of buprenorphine, whereas knockout of the KOR abolished the antidepressant-like effects of the drug, supporting the notion that the antidepressant-like effects of buprenorphine are indeed mediated by modulation of the KOR by the drug (and not of the MOR, DOR, or NOP).[26] However, a subsequent study found that the MOR may play an important role in the antidepressant-like effects of buprenorphine in animals.[27]

Buprenorphine is not a silent antagonist of the KOR but rather a weak partial agonist.[28][29] In vitro, it has shown some activation of the KOR at concentrations of ≥ 100 nM, with an Emax of 22% at 30 μM; no plateau in maximal response (EC50) was observed at concentrations up to 30 μM.[29] Samidorphan similarly shows activation of the KOR in vitro, but to an even greater extent, with an EC50 of 3.3 nM and an Emax of 36%.[13][14] As such, ALKS-5461 may possess both antagonistic and agonistic potential at the KOR.[28] Because antagonism of the KOR seems to be responsible for the antidepressant effects of ALKS-5461, this property could in theory limit the effectiveness of ALKS-5461 in the treatment of depression.[26][30]

History edit

ALKS-5461 was granted Fast Track Designation by the Food and Drug Administration (FDA) for treatment-resistant depression in October 2013.[31] During June and July 2014, three phase III clinical trials were initiated in the United States for treatment-resistant depression.[1] Alkermes reported that the first two trials failed in 2016.[1][3] In August 2017, based on the third trial, Alkermes announced the initiation of a rolling submission of a New Drug Application for ALKS-5461 to the FDA.[4] On 31 January 2018, Alkermes submitted a New Drug Application for ALKS-5461 to the FDA for the adjunctive treatment of major depressive disorder.[32] The submission was accepted by the FDA on 9 April 2018 after initially serving a refuse-to-file letter due to insufficient evidence of overall effectiveness.[33]

In November 2018, an FDA advisory committee voted 21–2 against recommending approval of ALKS-5461 for MDD, setting the medication up for likely rejection.[5] The main reason cited was insufficient evidence of effectiveness.[5] The panel voted in favor of adequate safety having been demonstrated.[5]

See also edit

References edit

  1. ^ a b c Dhir A (January 2017). "Investigational drugs for treating major depressive disorder". Expert Opinion on Investigational Drugs. 26 (1): 9–24. doi:10.1080/13543784.2017.1267727. PMID 27960559. S2CID 45232796.
  2. ^ Machado-Vieira R, Henter ID, Zarate CA (May 2017). "New targets for rapid antidepressant action". Progress in Neurobiology. 152: 21–37. doi:10.1016/j.pneurobio.2015.12.001. PMC 4919246. PMID 26724279.
  3. ^ a b Steele A (21 January 2016). "Alkermes Depression Drug Disappoints in Trials". WSJ. Retrieved 21 January 2016.
  4. ^ a b Taylor P (August 21, 2017). "Will third trial be the charm for Alkermes' depression drug?". FierceBiotech.
  5. ^ a b c d Al Idrus A (2 November 2018). "FDA panel slams Alkermes' opioid-based depression drug". Fierce Biotech.
  6. ^ "FDA declines to approve Alkermes opioid-based depression drug". Reuters. 1 February 2019. Retrieved 4 February 2019.
  7. ^ Kress HG (March 2009). "Clinical update on the pharmacology, efficacy and safety of transdermal buprenorphine". European Journal of Pain. 13 (3): 219–230. doi:10.1016/j.ejpain.2008.04.011. PMID 18567516. S2CID 8243410.
  8. ^ Lutfy K, Cowan A (October 2004). "Buprenorphine: a unique drug with complex pharmacology". Current Neuropharmacology. 2 (4): 395–402. doi:10.2174/1570159043359477. PMC 2581407. PMID 18997874.
  9. ^ a b Ehrich E, Turncliff R, Du Y, Leigh-Pemberton R, Fernandez E, Jones R, Fava M (May 2015). "Evaluation of opioid modulation in major depressive disorder". Neuropsychopharmacology. 40 (6): 1448–1455. doi:10.1038/npp.2014.330. PMC 4397403. PMID 25518754.
  10. ^ Khroyan TV, Wu J, Polgar WE, Cami-Kobeci G, Fotaki N, Husbands SM, Toll L (January 2015). "BU08073 a buprenorphine analogue with partial agonist activity at μ-receptors in vitro but long-lasting opioid antagonist activity in vivo in mice". British Journal of Pharmacology. 172 (2): 668–680. doi:10.1111/bph.12796. PMC 4292977. PMID 24903063.
  11. ^ Almarsson, O., Deaver, D., Turncliff, R., Wentland, M., & Ehrich, E. (2010). Discovery and early development of ALKS-33, an opioid modulator for treatment of reward disorders. Abstracts Of Papers Of The American Chemical Society, 240
  12. ^ a b Rorick-Kehn LM, Witkin JM, Statnick MA, Eberle EL, McKinzie JH, Kahl SD, et al. (February 2014). "LY2456302 is a novel, potent, orally-bioavailable small molecule kappa-selective antagonist with activity in animal models predictive of efficacy in mood and addictive disorders". Neuropharmacology. 77: 131–144. doi:10.1016/j.neuropharm.2013.09.021. PMID 24071566. S2CID 3230414.
  13. ^ a b Dwoskin LP (29 January 2014). Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Elsevier Science. pp. 398–399, 402–403. ISBN 978-0-12-420177-4.
  14. ^ a b Wentland MP, Lou R, Lu Q, Bu Y, Denhardt C, Jin J, et al. (April 2009). "Syntheses of novel high affinity ligands for opioid receptors". Bioorganic & Medicinal Chemistry Letters. 19 (8): 2289–2294. doi:10.1016/j.bmcl.2009.02.078. PMC 2791460. PMID 19282177.
  15. ^ Su TP (January 1985). "Further demonstration of kappa opioid binding sites in the brain: evidence for heterogeneity". The Journal of Pharmacology and Experimental Therapeutics. 232 (1): 144–148. PMID 2856939.
  16. ^ Leander JD (September 1987). "Buprenorphine has potent kappa opioid receptor antagonist activity". Neuropharmacology. 26 (9): 1445–1447. doi:10.1016/0028-3908(87)90112-2. PMID 2823167. S2CID 43382591.
  17. ^ a b c Shippenberg TS (January 2009). "The dynorphin/kappa opioid receptor system: a new target for the treatment of addiction and affective disorders?". Neuropsychopharmacology. 34 (1): 247. doi:10.1038/npp.2008.165. PMID 19079072.
  18. ^ a b Rankovic Z, Hargreaves R, Bingham M (2012). Drug Discovery for Psychiatric Disorders. Royal Society of Chemistry. pp. 314–317. ISBN 978-1-84973-365-6.
  19. ^ Pfeiffer A, Brantl V, Herz A, Emrich HM (August 1986). "Psychotomimesis mediated by kappa opiate receptors". Science. 233 (4765): 774–776. Bibcode:1986Sci...233..774P. doi:10.1126/science.3016896. PMID 3016896. S2CID 37512800.
  20. ^ Yan F, Roth BL (October 2004). "Salvinorin A: a novel and highly selective kappa-opioid receptor agonist". Life Sciences. 75 (22): 2615–2619. doi:10.1016/j.lfs.2004.07.008. PMID 15369697.
  21. ^ a b Land BB, Bruchas MR, Lemos JC, Xu M, Melief EJ, Chavkin C (January 2008). "The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system". The Journal of Neuroscience. 28 (2): 407–414. doi:10.1523/JNEUROSCI.4458-07.2008. PMC 2612708. PMID 18184783.
  22. ^ Knoll AT, Carlezon WA (February 2010). "Dynorphin, stress, and depression". Brain Research. 1314: 56–73. doi:10.1016/j.brainres.2009.09.074. PMC 2819644. PMID 19782055.
  23. ^ McLaughlin JP, Marton-Popovici M, Chavkin C (July 2003). "Kappa opioid receptor antagonism and prodynorphin gene disruption block stress-induced behavioral responses". The Journal of Neuroscience. 23 (13): 5674–5683. doi:10.1523/JNEUROSCI.23-13-05674.2003. PMC 2104777. PMID 12843270.
  24. ^ Urbano M, Guerrero M, Rosen H, Roberts E (May 2014). "Antagonists of the kappa opioid receptor". Bioorganic & Medicinal Chemistry Letters. 24 (9): 2021–2032. doi:10.1016/j.bmcl.2014.03.040. PMID 24690494.
  25. ^ Carlezon WA, Béguin C, Knoll AT, Cohen BM (September 2009). "Kappa-opioid ligands in the study and treatment of mood disorders". Pharmacology & Therapeutics. 123 (3): 334–343. doi:10.1016/j.pharmthera.2009.05.008. PMC 2740476. PMID 19497337.
  26. ^ a b Falcon E, Browne CA, Leon RM, Fleites VC, Sweeney R, Kirby LG, Lucki I (August 2016). "Antidepressant-like Effects of Buprenorphine are Mediated by Kappa Opioid Receptors". Neuropsychopharmacology. 41 (9): 2344–2351. doi:10.1038/npp.2016.38. PMC 4946065. PMID 26979295.
  27. ^ Robinson SA, Erickson RL, Browne CA, Lucki I (February 2017). "A role for the mu opioid receptor in the antidepressant effects of buprenorphine". Behavioural Brain Research. 319: 96–103. doi:10.1016/j.bbr.2016.10.050. PMC 5587126. PMID 27818236.
  28. ^ a b Fava M, Memisoglu A, Thase ME, Bodkin JA, Trivedi MH, de Somer M, et al. (May 2016). "Opioid Modulation With Buprenorphine/Samidorphan as Adjunctive Treatment for Inadequate Response to Antidepressants: A Randomized Double-Blind Placebo-Controlled Trial". The American Journal of Psychiatry. 173 (5): 499–508. doi:10.1176/appi.ajp.2015.15070921. PMID 26869247.
  29. ^ a b Zhu J, Luo LY, Li JG, Chen C, Liu-Chen LY (August 1997). "Activation of the cloned human kappa opioid receptor by agonists enhances [35S]GTPgammaS binding to membranes: determination of potencies and efficacies of ligands". The Journal of Pharmacology and Experimental Therapeutics. 282 (2): 676–684. PMID 9262330.
  30. ^ Falcon E, Maier K, Robinson SA, Hill-Smith TE, Lucki I (March 2015). "Effects of buprenorphine on behavioral tests for antidepressant and anxiolytic drugs in mice". Psychopharmacology. 232 (5): 907–915. doi:10.1007/s00213-014-3723-y. PMC 4326609. PMID 25178815.
  31. ^ "Alkermes Receives Fast Track Designation for ALKS 5461 for Major Depressive Disorder". Business Wire. 2013.
  32. ^ "Alkermes Submits New Drug Application To U.S. FDA For ALKS 5461 For The Adjunctive Treatment Of Major Depressive Disorder". Alkermes PLC (Press release). January 31, 2018 – via prnewswire.
  33. ^ Al Idrus A (16 April 2018). "Plot twist: FDA pivots on Alkermes' depression drug". FierceBiotech. Retrieved 2018-04-23.

Further reading edit

  • Peciña M, Karp JF, Mathew S, Todtenkopf MS, Ehrich EW, Zubieta JK (April 2019). "Endogenous opioid system dysregulation in depression: implications for new therapeutic approaches". Molecular Psychiatry. 24 (4): 576–587. doi:10.1038/s41380-018-0117-2. PMC 6310672. PMID 29955162.

External links edit

  • "Buprenorphine/samidorphan". AdisInsight. Springer Nature Switzerland AG.

January 01, 1970
buprenorphine, samidorphan, developmental, code, name, alks, 5461, combination, formulation, buprenorphine, samidorphan, which, under, development, antidepressants, treatment, resistant, depression, buprenorphine, samidorphan, bottom, combination, ofbuprenorph. Buprenorphine samidorphan developmental code name ALKS 5461 is a combination formulation of buprenorphine and samidorphan which is under development as an add on to antidepressants in treatment resistant depression TRD 2 Buprenorphine samidorphanBuprenorphine top samidorphan bottom Combination ofBuprenorphineOpioid modulatorSamidorphanOpioid antagonistClinical dataOther namesALKS 5461Routes ofadministrationSublingual 1 Legal statusLegal statusUS Investigational New DrugIdentifiersCAS Number2415438 51 4 ALKS 5461 failed to meet its primary efficacy endpoints in two trials from 2016 3 On the basis of a third study that did meet its primary endpoints Alkermes initiated a rolling New Drug Application with the FDA 4 In November 2018 an FDA panel voted against recommending approval finding that evidence was insufficient 5 As such approval of the medication was rejected in 2019 6 It is a k opioid receptor KOR antagonist and is being developed by Alkermes Contents 1 Pharmacology 1 1 Pharmacodynamics 1 1 1 k Opioid receptor antagonism 2 History 3 See also 4 References 5 Further reading 6 External linksPharmacology editSee also Buprenorphine Pharmacology and Samidorphan Pharmacology Pharmacodynamics edit ALKS 5461 is a 1 1 ratio combination of 1 buprenorphine a weak partial agonist of the m opioid receptor MOR antagonist very weak partial agonist of the k opioid receptor KOR and to a lesser extent antagonist of the d opioid receptor DOR and weak partial agonist of the nociceptin receptor NOP 7 8 9 10 and 2 samidorphan a preferential antagonist of the MOR but also to a slightly lesser extent weak partial agonist of the KOR and DOR 11 12 13 14 The combination of these two drugs putatively results in what is functionally a blockade of KORs with negligible activation of MORs 9 12 k Opioid receptor antagonism edit It has been known since the 1980s that buprenorphine binds to at high affinity and antagonizes the KOR 15 16 Through activation of the KOR dynorphins opioid peptides that are the endogenous ligands of the KOR and that can in many regards be figuratively thought of as functional inverses of the morphine like euphoric and stress inhibiting endorphins 17 induce dysphoria and stress like responses in both animals and humans 18 as well as psychotomimetic effects in humans 19 20 and are thought to be essential for the mediation of the dysphoric aspects of stress 21 In addition dynorphins are believed to be critically involved in producing the changes in neuroplasticity evoked by chronic stress that lead to the development of depressive and anxiety disorders increased drug seeking behavior and dysregulation of the hypothalamic pituitary adrenal HPA axis 17 21 22 In support of this in knockout mice lacking the genes encoding the KOR and or prodynorphin the endogenous precursor of the dynorphins many of the usual effects of exposure to chronic stress are completely absent such as increased immobility in the forced swimming test a widely employed assay of depressive like behavior and increased conditioned place preference for cocaine a measure of the rewarding properties and addictive susceptibility to cocaine 23 Accordingly KOR antagonists show robust efficacy in animal models of depression anxiety anhedonia drug addiction and other stress related behavioral and physiological abnormalities 17 18 24 25 A mouse study found that knockout of the MOR or DOR or selective pharmacological ablation of the NOP did not affect the antidepressant like effects of buprenorphine whereas knockout of the KOR abolished the antidepressant like effects of the drug supporting the notion that the antidepressant like effects of buprenorphine are indeed mediated by modulation of the KOR by the drug and not of the MOR DOR or NOP 26 However a subsequent study found that the MOR may play an important role in the antidepressant like effects of buprenorphine in animals 27 Buprenorphine is not a silent antagonist of the KOR but rather a weak partial agonist 28 29 In vitro it has shown some activation of the KOR at concentrations of 100 nM with an Emax of 22 at 30 mM no plateau in maximal response EC50 was observed at concentrations up to 30 mM 29 Samidorphan similarly shows activation of the KOR in vitro but to an even greater extent with an EC50 of 3 3 nM and an Emax of 36 13 14 As such ALKS 5461 may possess both antagonistic and agonistic potential at the KOR 28 Because antagonism of the KOR seems to be responsible for the antidepressant effects of ALKS 5461 this property could in theory limit the effectiveness of ALKS 5461 in the treatment of depression 26 30 History editALKS 5461 was granted Fast Track Designation by the Food and Drug Administration FDA for treatment resistant depression in October 2013 31 During June and July 2014 three phase III clinical trials were initiated in the United States for treatment resistant depression 1 Alkermes reported that the first two trials failed in 2016 1 3 In August 2017 based on the third trial Alkermes announced the initiation of a rolling submission of a New Drug Application for ALKS 5461 to the FDA 4 On 31 January 2018 Alkermes submitted a New Drug Application for ALKS 5461 to the FDA for the adjunctive treatment of major depressive disorder 32 The submission was accepted by the FDA on 9 April 2018 after initially serving a refuse to file letter due to insufficient evidence of overall effectiveness 33 In November 2018 an FDA advisory committee voted 21 2 against recommending approval of ALKS 5461 for MDD setting the medication up for likely rejection 5 The main reason cited was insufficient evidence of effectiveness 5 The panel voted in favor of adequate safety having been demonstrated 5 See also editk Opioid receptor Antagonists List of investigational antidepressantsReferences edit a b c Dhir A January 2017 Investigational drugs for treating major depressive disorder Expert Opinion on Investigational Drugs 26 1 9 24 doi 10 1080 13543784 2017 1267727 PMID 27960559 S2CID 45232796 Machado Vieira R Henter ID Zarate CA May 2017 New targets for rapid antidepressant action Progress in Neurobiology 152 21 37 doi 10 1016 j pneurobio 2015 12 001 PMC 4919246 PMID 26724279 a b Steele A 21 January 2016 Alkermes Depression Drug Disappoints in Trials WSJ Retrieved 21 January 2016 a b Taylor P August 21 2017 Will third trial be the charm for Alkermes depression drug FierceBiotech a b c d Al Idrus A 2 November 2018 FDA panel slams Alkermes opioid based depression drug Fierce Biotech FDA declines to approve Alkermes opioid based depression drug Reuters 1 February 2019 Retrieved 4 February 2019 Kress HG March 2009 Clinical update on the pharmacology efficacy and safety of transdermal buprenorphine European Journal of Pain 13 3 219 230 doi 10 1016 j ejpain 2008 04 011 PMID 18567516 S2CID 8243410 Lutfy K Cowan A October 2004 Buprenorphine a unique drug with complex pharmacology Current Neuropharmacology 2 4 395 402 doi 10 2174 1570159043359477 PMC 2581407 PMID 18997874 a b Ehrich E Turncliff R Du Y Leigh Pemberton R Fernandez E Jones R Fava M May 2015 Evaluation of opioid modulation in major depressive disorder Neuropsychopharmacology 40 6 1448 1455 doi 10 1038 npp 2014 330 PMC 4397403 PMID 25518754 Khroyan TV Wu J Polgar WE Cami Kobeci G Fotaki N Husbands SM Toll L January 2015 BU08073 a buprenorphine analogue with partial agonist activity at m receptors in vitro but long lasting opioid antagonist activity in vivo in mice British Journal of Pharmacology 172 2 668 680 doi 10 1111 bph 12796 PMC 4292977 PMID 24903063 Almarsson O Deaver D Turncliff R Wentland M amp Ehrich E 2010 Discovery and early development of ALKS 33 an opioid modulator for treatment of reward disorders Abstracts Of Papers Of The American Chemical Society 240 a b Rorick Kehn LM Witkin JM Statnick MA Eberle EL McKinzie JH Kahl SD et al February 2014 LY2456302 is a novel potent orally bioavailable small molecule kappa selective antagonist with activity in animal models predictive of efficacy in mood and addictive disorders Neuropharmacology 77 131 144 doi 10 1016 j neuropharm 2013 09 021 PMID 24071566 S2CID 3230414 a b Dwoskin LP 29 January 2014 Emerging Targets amp Therapeutics in the Treatment of Psychostimulant Abuse Elsevier Science pp 398 399 402 403 ISBN 978 0 12 420177 4 a b Wentland MP Lou R Lu Q Bu Y Denhardt C Jin J et al April 2009 Syntheses of novel high affinity ligands for opioid receptors Bioorganic amp Medicinal Chemistry Letters 19 8 2289 2294 doi 10 1016 j bmcl 2009 02 078 PMC 2791460 PMID 19282177 Su TP January 1985 Further demonstration of kappa opioid binding sites in the brain evidence for heterogeneity The Journal of Pharmacology and Experimental Therapeutics 232 1 144 148 PMID 2856939 Leander JD September 1987 Buprenorphine has potent kappa opioid receptor antagonist activity Neuropharmacology 26 9 1445 1447 doi 10 1016 0028 3908 87 90112 2 PMID 2823167 S2CID 43382591 a b c Shippenberg TS January 2009 The dynorphin kappa opioid receptor system a new target for the treatment of addiction and affective disorders Neuropsychopharmacology 34 1 247 doi 10 1038 npp 2008 165 PMID 19079072 a b Rankovic Z Hargreaves R Bingham M 2012 Drug Discovery for Psychiatric Disorders Royal Society of Chemistry pp 314 317 ISBN 978 1 84973 365 6 Pfeiffer A Brantl V Herz A Emrich HM August 1986 Psychotomimesis mediated by kappa opiate receptors Science 233 4765 774 776 Bibcode 1986Sci 233 774P doi 10 1126 science 3016896 PMID 3016896 S2CID 37512800 Yan F Roth BL October 2004 Salvinorin A a novel and highly selective kappa opioid receptor agonist Life Sciences 75 22 2615 2619 doi 10 1016 j lfs 2004 07 008 PMID 15369697 a b Land BB Bruchas MR Lemos JC Xu M Melief EJ Chavkin C January 2008 The dysphoric component of stress is encoded by activation of the dynorphin kappa opioid system The Journal of Neuroscience 28 2 407 414 doi 10 1523 JNEUROSCI 4458 07 2008 PMC 2612708 PMID 18184783 Knoll AT Carlezon WA February 2010 Dynorphin stress and depression Brain Research 1314 56 73 doi 10 1016 j brainres 2009 09 074 PMC 2819644 PMID 19782055 McLaughlin JP Marton Popovici M Chavkin C July 2003 Kappa opioid receptor antagonism and prodynorphin gene disruption block stress induced behavioral responses The Journal of Neuroscience 23 13 5674 5683 doi 10 1523 JNEUROSCI 23 13 05674 2003 PMC 2104777 PMID 12843270 Urbano M Guerrero M Rosen H Roberts E May 2014 Antagonists of the kappa opioid receptor Bioorganic amp Medicinal Chemistry Letters 24 9 2021 2032 doi 10 1016 j bmcl 2014 03 040 PMID 24690494 Carlezon WA Beguin C Knoll AT Cohen BM September 2009 Kappa opioid ligands in the study and treatment of mood disorders Pharmacology amp Therapeutics 123 3 334 343 doi 10 1016 j pharmthera 2009 05 008 PMC 2740476 PMID 19497337 a b Falcon E Browne CA Leon RM Fleites VC Sweeney R Kirby LG Lucki I August 2016 Antidepressant like Effects of Buprenorphine are Mediated by Kappa Opioid Receptors Neuropsychopharmacology 41 9 2344 2351 doi 10 1038 npp 2016 38 PMC 4946065 PMID 26979295 Robinson SA Erickson RL Browne CA Lucki I February 2017 A role for the mu opioid receptor in the antidepressant effects of buprenorphine Behavioural Brain Research 319 96 103 doi 10 1016 j bbr 2016 10 050 PMC 5587126 PMID 27818236 a b Fava M Memisoglu A Thase ME Bodkin JA Trivedi MH de Somer M et al May 2016 Opioid Modulation With Buprenorphine Samidorphan as Adjunctive Treatment for Inadequate Response to Antidepressants A Randomized Double Blind Placebo Controlled Trial The American Journal of Psychiatry 173 5 499 508 doi 10 1176 appi ajp 2015 15070921 PMID 26869247 a b Zhu J Luo LY Li JG Chen C Liu Chen LY August 1997 Activation of the cloned human kappa opioid receptor by agonists enhances 35S GTPgammaS binding to membranes determination of potencies and efficacies of ligands The Journal of Pharmacology and Experimental Therapeutics 282 2 676 684 PMID 9262330 Falcon E Maier K Robinson SA Hill Smith TE Lucki I March 2015 Effects of buprenorphine on behavioral tests for antidepressant and anxiolytic drugs in mice Psychopharmacology 232 5 907 915 doi 10 1007 s00213 014 3723 y PMC 4326609 PMID 25178815 Alkermes Receives Fast Track Designation for ALKS 5461 for Major Depressive Disorder Business Wire 2013 Alkermes Submits New Drug Application To U S FDA For ALKS 5461 For The Adjunctive Treatment Of Major Depressive Disorder Alkermes PLC Press release January 31 2018 via prnewswire Al Idrus A 16 April 2018 Plot twist FDA pivots on Alkermes depression drug FierceBiotech Retrieved 2018 04 23 Further reading editPecina M Karp JF Mathew S Todtenkopf MS Ehrich EW Zubieta JK April 2019 Endogenous opioid system dysregulation in depression implications for new therapeutic approaches Molecular Psychiatry 24 4 576 587 doi 10 1038 s41380 018 0117 2 PMC 6310672 PMID 29955162 External links edit Buprenorphine samidorphan AdisInsight Springer Nature Switzerland AG Retrieved from https en wikipedia org w index php title Buprenorphine samidorphan amp oldid 1183561414, wikipedia, wiki, book, books, library,

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