Chemistry:AZD-1134

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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-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.[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-HT1B 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-HT1B 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

  1. ↑ 1.0 1.1 1.2 "AZD 1134". 31 March 2004. https://adisinsight.springer.com/drugs/800017898. 
  2. ↑ 2.0 2.1 "P.1.016 In vivo pharmacology of AZD1134, a novel 5-HT1B antagonist". European Neuropsychopharmacology 13: S181–S182. 2003. doi:10.1016/S0924-977X(03)91727-5. 
  3. ↑ 3.0 3.1 3.2 3.3 "P.1.094 AZD1134, a high affinity 5-HT1B receptor antagonist activates serotonin turnover and release in guinea pig brain". European Neuropsychopharmacology 13: S214. 2003. doi:10.1016/S0924-977X(03)91804-9. 
  4. ↑ "[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. July 2009. doi:10.1124/jpet.109.150722. PMID 19401496. 
  5. ↑ "Preclinical pharmacology and pharmacokinetics of AZD3783, a selective 5-hydroxytryptamine 1B receptor antagonist". J Pharmacol Exp Ther 339 (2): 567–578. November 2011. doi:10.1124/jpet.110.174433. PMID 21825000. 
  6. ↑ "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. February 2011. doi:10.1007/s00213-011-2165-z. PMID 21234549. 
  7. ↑ "Pathology and Neurotoxicity in Dogs after Repeat Dose Exposure to a Serotonin 5-HT1B Inhibitor". J Toxicol Pathol 27 (1): 31–42. April 2014. doi:10.1293/tox.2013-0033. PMID 24791065. 




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