Chemistry:O-Phenyl-3-iodotyramine

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Short description: Chemical compound


o-Phenyl-3-iodotyramine
Clinical data
Other nameso-PIT; o-Phenyl-iodotyramine; o-Phenyliodotyramine
Drug classTrace amine-associated receptor 1 (TAAR1) agonist
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
FormulaC14H14INO
Molar mass339.176 g·mol−1
3D model (JSmol)

o-Phenyl-3-iodotyramine (o-PIT) is a drug which acts as a selective agonist for the trace amine-associated receptor 1 (TAAR1).[1] It has reasonable selectivity for TAAR1 but relatively low potency, and is rapidly metabolised in vivo, making it less useful for research than newer ligands such as RO5166017.[2][3][4][5] Its EC50 values have been reported to be 35 nM for the mouse TAAR1,[4][6] 2.4 nM at the rat TAAR1,[6] and 9.5 nM at the human TAAR1.[5]

o-PIT has been found to produce effects in animals including hypothermia, hypolocomotion, antidepressant-like effects, anxiolytic-like effects, anti-obsessional-like effects, and antipsychotic-like effects, and inhibition of prepulse inhibition (PPI).[1][5][7] These actions may be partially to fully dependent on TAAR1 agonism depending on the effect in question.[5]

TAAR1 agonism has been implicated in modulating the effects of monoamine releasing agents (MRAs) like amphetamines.[8] The MRA 3,4-methylenedioxymethamphetamine (MDMA) is a potent agonist of the mouse TAAR1, whereas the MRA para-chloroamphetamine (PCA) is not a significant agonist of the human TAAR1 or presumably of the mouse TAAR1.[5][9] MDMA-induced in-vivo brain serotonin and dopamine release and hyperlocomotion are augmented in TAAR1 knockout mice relative to normal mice, whereas the in-vivo brain serotonin and dopamine release of PCA are not different between normal mice and TAAR1 knockout mice.[5][10] In the same study, o-PIT blunted the dopamine and serotonin release of PCA in mouse synaptosomes in vitro, an effect that was absent in synaptosomes from TAAR1 knockout mice.[5][10] These findings led to conclusions that TAAR1 agonism by MDMA auto-inhibits and constrains its own effects in rodents.[10][5] Although MDMA is a potent TAAR1 agonist in rodents, it is a very weak and non-significant TAAR1 agonist in humans.[9][11][12][13]

References

  1. ↑ 1.0 1.1 "Regulation of Monoaminergic Functions by Gpcrs with a Special Emphasis on Mental and Movement Disorders". 2022. https://www.proquest.com/openview/943b26a4730cac83e9138e137d887a4b/1?pq-origsite=gscholar&cbl=2026366&diss=y.  At: Karolinska Institutet.
  2. ↑ "Trace amine-associated receptors and their ligands". British Journal of Pharmacology 149 (8): 967–978. December 2006. doi:10.1038/sj.bjp.0706948. PMID 17088868. 
  3. ↑ "Trace amines depress D(2)-autoreceptor-mediated responses on midbrain dopaminergic cells". British Journal of Pharmacology 160 (6): 1509–1520. July 2010. doi:10.1111/j.1476-5381.2010.00792.x. PMID 20590640. 
  4. ↑ 4.0 4.1 "TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity". Proceedings of the National Academy of Sciences of the United States of America 108 (20): 8485–8490. May 2011. doi:10.1073/pnas.1103029108. PMID 21525407. Bibcode: 2011PNAS..108.8485R. "RO5166017 exhibits high binding affinity for TAAR1 and high potency to stimulate cAMP production, particularly at rodent TAAR1. Compared with pTyr, RO5166017 exhibited 200- fold higher affinity (Ki = 1.9 vs. 404 nM) and potency to activate cAMP production (EC50 = 3.3 vs. 545 nM) at mouse TAAR1 (17), whereas T1AM and its derivative o-phenyl-3-iodotyramine show EC50 values of 112 and 35 nM, respectively (30).". 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 "Genetic deletion of trace amine 1 receptors reveals their role in auto-inhibiting the actions of ecstasy (MDMA)". J Neurosci 31 (47): 16928–16940. November 2011. doi:10.1523/JNEUROSCI.2502-11.2011. PMID 22114263. 
  6. ↑ 6.0 6.1 "Trace amine-associated receptor agonists: synthesis and evaluation of thyronamines and related analogues". J Med Chem 49 (3): 1101–1112. February 2006. doi:10.1021/jm0505718. PMID 16451074. 
  7. ↑ "Trace Amine-Associated Receptor 1 Contributes to Diverse Functional Actions of O-Phenyl-Iodotyramine in Mice but Not to the Effects of Monoamine-Based Antidepressants". Int J Mol Sci 22 (16). August 2021. doi:10.3390/ijms22168907. PMID 34445611. 
  8. ↑ "Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction". Eur J Pharmacol 761: 345–352. August 2015. doi:10.1016/j.ejphar.2015.06.019. PMID 26092759. 
  9. ↑ 9.0 9.1 "Trace Amines and Their Receptors". Pharmacol Rev 70 (3): 549–620. July 2018. doi:10.1124/pr.117.015305. PMID 29941461. 
  10. ↑ 10.0 10.1 10.2 "Striatal Tyrosine Hydroxylase Is Stimulated via TAAR1 by 3-Iodothyronamine, But Not by Tyramine or β-Phenylethylamine". Front Pharmacol 9: 166. 2018. doi:10.3389/fphar.2018.00166. PMID 29545750. "Di Cara et al. (2011) showed that TAAR1 decreases the amplitude of Methylenedioxymethamphetamine (MDMA) induced dopamine release both in ventral and dorsal striatum. In the same study it was observed that the TAAR1 agonist, o-phenyl-3-iodotyramine (o-PIT) blunted the para-chloroamphetamine (PCA) induced dopamine release in both structures (Di Cara et al., 2011).". 
  11. ↑ "In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1". J Pharmacol Exp Ther 357 (1): 134–144. April 2016. doi:10.1124/jpet.115.229765. PMID 26791601. 
  12. ↑ "Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class". Bioorganic & Medicinal Chemistry 19 (23): 7044–7048. December 2011. doi:10.1016/j.bmc.2011.10.007. PMID 22037049. 
  13. ↑ "Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine". ACS Chem Neurosci 9 (10): 2408–2427. October 2018. doi:10.1021/acschemneuro.8b00155. PMID 30001118. PMC 6197894. https://shaunlacob.com/wp-content/uploads/2020/12/DC-MDMA.pdf. "[...] it is unclear if TAAR1 plays any role in the effects of MDMA in humans, as MDMA does not activate human TAAR1 in cellular assays like it does mouse and rat TAAR1.84". 




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