Chemistry:Pseudophenmetrazine

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Pseudophenmetrazine is a psychostimulant of the phenylmorpholine group. It is the N-demethylated and cis-configured analogue of phendimetrazine as well as the cis-configured stereoisomer of phenmetrazine.[1] In addition, along with phenmetrazine, it is believed to be one of the active metabolites of phendimetrazine, which itself is inactive and behaves merely as a prodrug.[2]

Relative to phenmetrazine, pseudophenmetrazine is of fairly low potency, acting as a modest releasing agent of norepinephrine (EC50 = 514 nM), while its (+)-enantiomer is a weak releaser of dopamine (EC50 = 1,457 nM) whereas its (−)-enantiomer is a weak reuptake inhibitor of dopamine (Ki = 2,691 nM);[2][3] together as a racemic mixture with the two enantiomers combined, pseudophenmetrazine behaves overall more as a dopamine reuptake inhibitor (Ki = 2,630 nM),[2][3] possibly due to the (+)-enantiomer blocking the uptake of the (−)-enantiomer into dopaminergic neurons and thus preventing it from inducing dopamine release. Neither enantiomer has any significant effect on serotonin reuptake or release (both Ki = >10,000 nM and EC50 = >10,000 nM, respectively).[2][3]

Monoamine release of pseudophenmetrazine and related agents (EC50, nM)
Compound NE DA 5-HT Ref
Phenethylamine 10.9 39.5 >10,000 [4][5][6]
Dextroamphetamine 6.6–10.2 5.8–24.8 698–1,765 [7][8][6][9]
Dextromethamphetamine 12.3–14.3 8.5–40.4 736–1,292 [7][10][6][9]
2-Phenylmorpholine 79 86 20,260 [11]
Phenmetrazine 29–50.4 70–131 7,765–>10,000 [12][6][13][11]
  (+)-Phenmetrazine 37.5 87.4 3246 [12]
  (–)-Phenmetrazine 62.9 415 >10,000 [12]
Phendimetrazine >10,000 >10,000 >100,000 [12][6][9]
Pseudophenmetrazine 514 >10,000 (RI) >10,000 [12]
  (+)-Pseudophenmetrazine 349 1,457 >10,000 [12]
  (–)-Pseudophenmetrazine 2,511 IA (RI) >10,000 [12]
Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. The assays were done in rat brain synaptosomes and human potencies may be different. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. Refs:[14][15]

References

  1. ↑ Dictionary of Pharmacological Agents. CRC Press. 1997. p. 1333. ISBN 978-0-412-46630-4. https://books.google.com/books?id=A0THacd46ZsC&pg=PA1333. Retrieved 18 May 2012. 
  2. ↑ 2.0 2.1 2.2 2.3 "Interaction of the anorectic medication, phendimetrazine, and its metabolites with monoamine transporters in rat brain". European Journal of Pharmacology 447 (1): 51–7. June 2002. doi:10.1016/S0014-2999(02)01830-7. PMID 12106802. https://zenodo.org/record/1259577. 
  3. ↑ 3.0 3.1 3.2 "Interaction of amphetamines and related compounds at the vesicular monoamine transporter". The Journal of Pharmacology and Experimental Therapeutics 319 (1): 237–46. October 2006. doi:10.1124/jpet.106.103622. PMID 16835371. 
  4. ↑ "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug Alcohol Depend 147: 1–19. February 2015. doi:10.1016/j.drugalcdep.2014.12.005. PMID 25548026. 
  5. ↑ Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines. 22 May 2012. https://scholarworks.uno.edu/td/1436/. Retrieved 4 November 2024. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 "Dopamine-releasing agents". Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. July 2008. pp. 305–320. ISBN 978-0-470-11790-3. OCLC 181862653. https://bitnest.netfirms.com/external/Books/Dopamine-releasing-agents_c11.pdf. 
  7. ↑ 7.0 7.1 "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse 39 (1): 32–41. January 2001. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707. 
  8. ↑ "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology 38 (4): 552–562. March 2013. doi:10.1038/npp.2012.204. PMID 23072836. 
  9. ↑ 9.0 9.1 9.2 "Profiling CNS Stimulants with a High-Throughput Assay for Biogenic Amine Transporter Substractes". Problems of Drug Dependence 1999: Proceedings of the 61st Annual Scientific Meeting, The College on Problems of Drug Dependence, Inc. NIDA Res Monogr. 180. 1999. pp. 1–476 (252). https://archives.nida.nih.gov/sites/default/files/180.pdf#page=261. "RESULTS. Methamphetamine and amphetamine potently released NE (IC50s = 14.3 and 7.0 nM) and DA (IC50s = 40.4 nM and 24.8 nM), and were much less potent releasers of 5-HT (IC50s = 740 nM and 1765 nM). Phentermine released all three biogenic amines with an order of potency NE (IC50 = 28.8 nM)> DA (IC50 = 262 nM)> 5-HT (IC50 = 2575 nM). Aminorex released NE (IC50 = 26.4 nM), DA (IC50 = 44.8 nM) and 5-HT (IC50 = 193 nM). Chlorphentermine was a very potent 5-HT releaser (IC50 = 18.2 nM), a weaker DA releaser (IC50 = 935 nM) and inactive in the NE release assay. Chlorphentermine was a moderate potency inhibitor of [3H]NE uptake (Ki = 451 nM). Diethylpropion, which is self-administered, was a weak DA uptake inhibitor (Ki = 15 µM) and NE uptake inhibitor (Ki = 18.1 µM) and essentially inactive in the other assays. Phendimetrazine, which is self-administered, was a weak DA uptake inhibitor (IC50 = 19 µM), a weak NE uptake inhibitor (8.3 µM) and essentially inactive in the other assays." 
  10. ↑ "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology 37 (5): 1192–1203. April 2012. doi:10.1038/npp.2011.304. PMID 22169943. 
  11. ↑ 11.0 11.1 "Phenylmorpholines and analogues thereof". 20 May 2011. https://patents.google.com/patent/WO2011146850A1/en. 
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 "Interaction of the anorectic medication, phendimetrazine, and its metabolites with monoamine transporters in rat brain". European Journal of Pharmacology 447 (1): 51–57. June 2002. doi:10.1016/s0014-2999(02)01830-7. PMID 12106802. 
  13. ↑ "Synthesis, analytical characterization, and monoamine transporter activity of the new psychoactive substance 4-methylphenmetrazine (4-MPM), with differentiation from its ortho- and meta- positional isomers". Drug Test Anal 10 (9): 1404–1416. September 2018. doi:10.1002/dta.2396. PMID 29673128. 
  14. ↑ "Monoamine transporters and psychostimulant drugs". European Journal of Pharmacology 479 (1–3): 23–40. October 2003. doi:10.1016/j.ejphar.2003.08.054. PMID 14612135. 
  15. ↑ "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry 6 (17): 1845–1859. 2006. doi:10.2174/156802606778249766. PMID 17017961. http://www.bentham-direct.org/pages/content.php?CTMC/2006/00000006/00000017/0004R.SGM. Retrieved 5 May 2020. 



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