AZD-1134

AZD-1134
Clinical data
Routes of; administration	Unspecified
Drug class	Serotonin 5-HT1B receptor antagonist
Identifiers
	IUPAC name 6-fluoro-8-(4-methylpiperazin-1-yl)-4-oxo-N-[4-(4-propanoylpiperazin-1-yl)phenyl]chromene-2-carboxamide;
CAS Number	442548-99-4;
PubChem CID	9830790;
ChemSpider	8006524;
UNII	GR7FP8T3TF;
ChEMBL	ChEMBL602674;
Chemical and physical data
Formula	C28H32FN5O4
Molar mass	521.593 g·mol−1
3D model (JSmol)	Interactive image;
	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.^[1]^[2]^[3]^[4] It is a selective serotonin 5-HT_1B 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.^[3] 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.^[3] The increases in serotonin levels and turnover with AZD-1134 are presumably due to blockade of inhibitory presynaptic 5-HT_1B autoreceptors.^[3] AZD-1134 administered alone produced antidepressant-like effects in animals.^[2]

History

AZD-1134 reached preclinical research prior to the discontinuation of its development.^[1] It was under development by AstraZeneca.^[1] Another selective serotonin 5-HT_1B receptor antagonist, AZD-3783, was also subsequently developed and studied by AstraZeneca.^[5]^[6] However, this drug was later found to produce unexpected neurotoxicity.^[7]

References

^ ^a ^b ^c ^d "AZD 1134". AdisInsight. 31 March 2004. Retrieved 11 December 2024.
^ ^a ^b 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.
^ ^a ^b ^c ^d 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.
^ Maier DL, Sobotka-Briner C, Ding M, Powell ME, Jiang Q, Hill G, et al. (July 2009). "[N-methyl-3H3]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.
^ 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.
^ 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 [11C]AZ10419369". Psychopharmacology (Berl). 213 (2–3): 533–545. doi:10.1007/s00213-011-2165-z. PMID 21234549.
^ 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.

[AdisInsight-1] "AZD 1134". AdisInsight. 31 March 2004. Retrieved 11 December 2024.

[HudzikSmolkaLitwin2003-2] 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.

[SmaginSongCross2003-3] 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.

[MaierSobotka-BrinerDing2009-4] Maier DL, Sobotka-Briner C, Ding M, Powell ME, Jiang Q, Hill G, et al. (July 2009). "[N-methyl-3H3]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.

[ZhangZhouWang2011-5] 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.

[VarnäsNybergKarlsson2011-6] 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 [11C]AZ10419369". Psychopharmacology (Berl). 213 (2–3): 533–545. doi:10.1007/s00213-011-2165-z. PMID 21234549.

[ChangCiaccioSchroeder2014-7] 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.

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AZD-1134

Pharmacology

History

References

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