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'''AZD-1134''' is a ] ] ] ] which was under development for the treatment ] and ]s but was never marketed.<ref name="AdisInsight">{{cite web | title=AZD 1134 | website=AdisInsight | date=31 March 2004 | url=https://adisinsight.springer.com/drugs/800017898 | access-date=11 December 2024}}</ref><ref name="HudzikSmolkaLitwin2003">{{cite journal | last=Hudzik | first=T. | last2=Smolka | first2=J. | last3=Litwin | first3=L. | last4=Porrey | first4=T. | last5=Pierson | first5=E. | title=P.1.016 In vivo pharmacology of AZD1134, a novel 5-HT1B antagonist | journal=European Neuropsychopharmacology | volume=13 | date=2003 | doi=10.1016/S0924-977X(03)91727-5 | pages=S181–S182}}</ref><ref name="SmaginSongCross2003">{{cite journal | last=Smagin | first=G.N. | last2=Song | first2=D. | last3=Cross | first3=A.J. | last4=Mrzljak | first4=L. | title=P.1.094 AZD1134, a high affinity 5-HT1B receptor antagonist activates serotonin turnover and release in guinea pig brain | journal=European Neuropsychopharmacology | volume=13 | date=2003 | doi=10.1016/S0924-977X(03)91804-9 | page=S214}}</ref><ref name="MaierSobotka-BrinerDing2009">{{cite journal | vauthors = Maier DL, Sobotka-Briner C, Ding M, Powell ME, Jiang Q, Hill G, Heys JR, Elmore CS, Pierson ME, Mrzljak L | title = AZ10419369 binding to the 5-HT1B receptor: in vitro characterization and in vivo receptor occupancy | journal = J Pharmacol Exp Ther | volume = 330 | issue = 1 | pages = 342–351 | date = July 2009 | pmid = 19401496 | doi = 10.1124/jpet.109.150722 | url = }}</ref> Its ] was unspecified.<ref name="AdisInsight" /> '''AZD-1134''' is an ] that was being evaluated for the treatment of ] and ] but was never marketed.<ref name="AdisInsight">{{cite web | title=AZD 1134 | website=AdisInsight | date=31 March 2004 | url=https://adisinsight.springer.com/drugs/800017898 | access-date=11 December 2024}}</ref><ref name="HudzikSmolkaLitwin2003">{{cite journal | vauthors = Hudzik T, Smolka J, Litwin L, Porrey T, Pierson E | title=P.1.016 In vivo pharmacology of AZD1134, a novel 5-HT1B antagonist | journal=European Neuropsychopharmacology | volume=13 | date=2003 | doi=10.1016/S0924-977X(03)91727-5 | pages=S181–S182}}</ref><ref name="SmaginSongCross2003">{{cite journal | vauthors = Smagin GN, Song D, Cross AJ, Mrzljak | title=P.1.094 AZD1134, a high affinity 5-HT1B receptor antagonist activates serotonin turnover and release in guinea pig brain | journal=European Neuropsychopharmacology | volume=13 | date=2003 | doi=10.1016/S0924-977X(03)91804-9 | page=S214}}</ref><ref name="MaierSobotka-BrinerDing2009">{{cite journal | vauthors = Maier DL, Sobotka-Briner C, Ding M, Powell ME, Jiang Q, Hill G, Heys JR, Elmore CS, Pierson ME, Mrzljak L | title = AZ10419369 binding to the 5-HT1B receptor: in vitro characterization and in vivo receptor occupancy | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 330 | issue = 1 | pages = 342–351 | date = July 2009 | pmid = 19401496 | doi = 10.1124/jpet.109.150722 }}</ref> It is a ] ] ] ].

== Pharmacology ==


The drug has been found to increase ] levels in the ] in animals and to increase serotonin ] (as measured by ]/serotonin ratio) in the ], ], ], and ].<ref name="SmaginSongCross2003" /> Alone, AZD-1134 increased hippocampal serotonin levels to 179% of baseline, and in combination with the ] (SSRI) ], it increased levels to 950% of baseline.<ref name="SmaginSongCross2003" /> The increases in serotonin levels and turnover with AZD-1134 are presumably due to blockade of ] ] 5-HT<sub>1B</sub> ]s.<ref name="SmaginSongCross2003" /> AZD-1134 administered alone produced ]-like effects in animals.<ref name="HudzikSmolkaLitwin2003" /> The drug has been found to increase ] levels in the ] in animals and to increase serotonin ] (as measured by ]/serotonin ratio) in the ], ], ], and ].<ref name="SmaginSongCross2003" /> Alone, AZD-1134 increased hippocampal serotonin levels to 179% of baseline, and in combination with the ] (SSRI) ], it increased levels to 950% of baseline.<ref name="SmaginSongCross2003" /> The increases in serotonin levels and turnover with AZD-1134 are presumably due to blockade of ] ] 5-HT<sub>1B</sub> ]s.<ref name="SmaginSongCross2003" /> AZD-1134 administered alone produced ]-like effects in animals.<ref name="HudzikSmolkaLitwin2003" />


== History ==
⚫ AZD-1134 reached ] prior to the discontinuation of its development.<ref name="AdisInsight" /> It was under development by ].<ref name="AdisInsight" /> Another selective serotonin 5-HT<sub>1B</sub> receptor antagonist, ], was also subsequently developed and studied by AstraZeneca.<ref name="ZhangZhouWang2011">{{cite journal | vauthors = Zhang M, Zhou D, Wang Y, Maier DL, Widzowski DV, Sobotka-Briner CD, Brockel BJ, Potts WM, Shenvi AB, Bernstein PR, Pierson ME | title = Preclinical pharmacology and pharmacokinetics of AZD3783, a selective 5-hydroxytryptamine 1B receptor antagonist | journal = J Pharmacol Exp Ther | volume = 339 | issue = 2 | pages = 567–578 | date = November 2011 | pmid = 21825000 | doi = 10.1124/jpet.110.174433 | url = }}</ref><ref name="VarnäsNybergKarlsson2011">{{cite journal | vauthors = Varnäs K, Nyberg S, Karlsson P, Pierson ME, Kågedal M, Cselényi Z, McCarthy D, Xiao A, Zhang M, Halldin C, Farde L | title = Dose-dependent binding of AZD3783 to brain 5-HT1B receptors in non-human primates and human subjects: a positron emission tomography study with AZ10419369 | journal = Psychopharmacology (Berl) | volume = 213 | issue = 2-3 | pages = 533–545 | date = February 2011 | pmid = 21234549 | doi = 10.1007/s00213-011-2165-z | url = }}</ref> However, this drug was later found to produce unexpected ].<ref name="ChangCiaccioSchroeder2014">{{cite journal | vauthors = Chang JC, Ciaccio P, Schroeder P, Wright L, Westwood R, Berg AL | title = Pathology and Neurotoxicity in Dogs after Repeat Dose Exposure to a Serotonin 5-HT1B Inhibitor | journal = J Toxicol Pathol | volume = 27 | issue = 1 | pages = 31–42 | date = April 2014 | pmid = 24791065 | pmc = 4000071 | doi = 10.1293/tox.2013-0033 | url = }}</ref>

⚫ AZD-1134 reached ] prior to the discontinuation of its development.<ref name="AdisInsight" /> It was under development by ].<ref name="AdisInsight" /> Another selective serotonin 5-HT<sub>1B</sub> receptor antagonist, ], was also subsequently developed and studied by AstraZeneca.<ref name="ZhangZhouWang2011">{{cite journal | vauthors = Zhang M, Zhou D, Wang Y, Maier DL, Widzowski DV, Sobotka-Briner CD, Brockel BJ, Potts WM, Shenvi AB, Bernstein PR, Pierson ME | title = Preclinical pharmacology and pharmacokinetics of AZD3783, a selective 5-hydroxytryptamine 1B receptor antagonist | journal = J Pharmacol Exp Ther | volume = 339 | issue = 2 | pages = 567–578 | date = November 2011 | pmid = 21825000 | doi = 10.1124/jpet.110.174433 | url = }}</ref><ref name="VarnäsNybergKarlsson2011">{{cite journal | vauthors = Varnäs K, Nyberg S, Karlsson P, Pierson ME, Kågedal M, Cselényi Z, McCarthy D, Xiao A, Zhang M, Halldin C, Farde L | title = Dose-dependent binding of AZD3783 to brain 5-HT1B receptors in non-human primates and human subjects: a positron emission tomography study with AZ10419369 | journal = Psychopharmacology (Berl) | volume = 213 | issue = 2–3 | pages = 533–545 | date = February 2011 | pmid = 21234549 | doi = 10.1007/s00213-011-2165-z | url = }}</ref> However, this drug was later found to produce unexpected ].<ref name="ChangCiaccioSchroeder2014">{{cite journal | vauthors = Chang JC, Ciaccio P, Schroeder P, Wright L, Westwood R, Berg AL | title = Pathology and Neurotoxicity in Dogs after Repeat Dose Exposure to a Serotonin 5-HT1B Inhibitor | journal = J Toxicol Pathol | volume = 27 | issue = 1 | pages = 31–42 | date = April 2014 | pmid = 24791065 | pmc = 4000071 | doi = 10.1293/tox.2013-0033 | url = }}</ref>


==References== ==References==
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Latest revision as of 22:57, 11 December 2024

Pharmaceutical compound
AZD-1134
Clinical data
Routes of
administration		Unspecified
Drug classSerotonin 5-HT1B receptor antagonist
Identifiers
IUPAC name
  • 6-fluoro-8-(4-methylpiperazin-1-yl)-4-oxo-N-chromene-2-carboxamide
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC28H32FN5O4
Molar mass521.593 g·mol
3D model (JSmol)
SMILES
  • CCC(=O)N1CCN(CC1)C2=CC=C(C=C2)NC(=O)C3=CC(=O)C4=C(O3)C(=CC(=C4)F)N5CCN(CC5)C
InChI
  • InChI=1S/C28H32FN5O4/c1-3-26(36)34-14-12-32(13-15-34)21-6-4-20(5-7-21)30-28(37)25-18-24(35)22-16-19(29)17-23(27(22)38-25)33-10-8-31(2)9-11-33/h4-7,16-18H,3,8-15H2,1-2H3,(H,30,37)
  • Key:CKBARMWSFIJZTL-UHFFFAOYSA-N

AZD-1134 is an investigational new drug that was being evaluated for the treatment of major depressive disorder and anxiety disorder but was never marketed. It is a selective serotonin 5-HT1B receptor antagonist.

Pharmacology

The drug has been found to increase serotonin levels in the dorsal hippocampus in animals and to increase serotonin turnover (as measured by 5-HIAA/serotonin ratio) in the cerebral cortex, hypothalamus, hippocampus, and striatum. Alone, AZD-1134 increased hippocampal serotonin levels to 179% of baseline, and in combination with the selective serotonin reuptake inhibitor (SSRI) citalopram, it increased levels to 950% of baseline. The increases in serotonin levels and turnover with AZD-1134 are presumably due to blockade of inhibitory presynaptic 5-HT1B autoreceptors. AZD-1134 administered alone produced antidepressant-like effects in animals.

History

AZD-1134 reached preclinical research prior to the discontinuation of its development. It was under development by AstraZeneca. Another selective serotonin 5-HT1B receptor antagonist, AZD-3783, was also subsequently developed and studied by AstraZeneca. However, this drug was later found to produce unexpected neurotoxicity.

References

  1. ^ "AZD 1134". AdisInsight. 31 March 2004. Retrieved 11 December 2024.
  2. ^ Hudzik T, Smolka J, Litwin L, Porrey T, Pierson E (2003). "P.1.016 In vivo pharmacology of AZD1134, a novel 5-HT1B antagonist". European Neuropsychopharmacology. 13: S181–S182. doi:10.1016/S0924-977X(03)91727-5.
  3. ^ Smagin GN, Song D, Cross AJ, Mrzljak (2003). "P.1.094 AZD1134, a high affinity 5-HT1B receptor antagonist activates serotonin turnover and release in guinea pig brain". European Neuropsychopharmacology. 13: S214. doi:10.1016/S0924-977X(03)91804-9.
  4. Maier DL, Sobotka-Briner C, Ding M, Powell ME, Jiang Q, Hill G, et al. (July 2009). "AZ10419369 binding to the 5-HT1B receptor: in vitro characterization and in vivo receptor occupancy". The Journal of Pharmacology and Experimental Therapeutics. 330 (1): 342–351. doi:10.1124/jpet.109.150722. PMID 19401496.
  5. Zhang M, Zhou D, Wang Y, Maier DL, Widzowski DV, Sobotka-Briner CD, et al. (November 2011). "Preclinical pharmacology and pharmacokinetics of AZD3783, a selective 5-hydroxytryptamine 1B receptor antagonist". J Pharmacol Exp Ther. 339 (2): 567–578. doi:10.1124/jpet.110.174433. PMID 21825000.
  6. Varnäs K, Nyberg S, Karlsson P, Pierson ME, Kågedal M, Cselényi Z, et al. (February 2011). "Dose-dependent binding of AZD3783 to brain 5-HT1B receptors in non-human primates and human subjects: a positron emission tomography study with AZ10419369". Psychopharmacology (Berl). 213 (2–3): 533–545. doi:10.1007/s00213-011-2165-z. PMID 21234549.
  7. Chang JC, Ciaccio P, Schroeder P, Wright L, Westwood R, Berg AL (April 2014). "Pathology and Neurotoxicity in Dogs after Repeat Dose Exposure to a Serotonin 5-HT1B Inhibitor". J Toxicol Pathol. 27 (1): 31–42. doi:10.1293/tox.2013-0033. PMC 4000071. PMID 24791065.


Serotonin receptor modulators
5-HT1
5-HT1A
5-HT1B
5-HT1D
5-HT1E
5-HT1F
5-HT2
5-HT2A
5-HT2B
5-HT2C
5-HT3–7
5-HT3
5-HT4
5-HT5A
5-HT6
5-HT7


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