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Pseudophenmetrazine

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Pseudophenmetrazine
Clinical data
ATC code
  • None
Identifiers
  • (±)-cis-3-methyl-2-phenylmorpholine
    or
    (±)-(2RS,3SR)-3-methyl-2-phenylmorpholine
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
FormulaC11H15NO
Molar mass177.247 g·mol−1
3D model (JSmol)
  • C[C@@H]1[C@@H](OCCN1)C2=CC=CC=C2
  • InChI=1S/C11H15NO/c1-9-11(13-8-7-12-9)10-5-3-2-4-6-10/h2-6,9,11-12H,7-8H2,1H3/t9-,11-/m1/s1
  • Key:OOBHFESNSZDWIU-MWLCHTKSSA-N

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 (EC50Tooltip Half maximal effective concentration, nM)
Compound NETooltip Norepinephrine DATooltip Dopamine 5-HTTooltip Serotonin 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

[edit]
  1. ^ Macdonald F (1997). Dictionary of Pharmacological Agents. CRC Press. p. 1333. ISBN 978-0-412-46630-4. Retrieved 18 May 2012.
  2. ^ a b c d Rothman RB, Katsnelson M, Vu N, et al. (June 2002). "Interaction of the anorectic medication, phendimetrazine, and its metabolites with monoamine transporters in rat brain". European Journal of Pharmacology. 447 (1): 51–7. doi:10.1016/S0014-2999(02)01830-7. PMID 12106802.
  3. ^ a b c Partilla JS, Dempsey AG, Nagpal AS, Blough BE, Baumann MH, Rothman RB (October 2006). "Interaction of amphetamines and related compounds at the vesicular monoamine transporter". The Journal of Pharmacology and Experimental Therapeutics. 319 (1): 237–46. CiteSeerX 10.1.1.690.6669. doi:10.1124/jpet.106.103622. PMID 16835371. S2CID 22730478.
  4. ^ Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, Partilla JS, Rothman RB, Katz JL (February 2015). "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug Alcohol Depend. 147: 1–19. doi:10.1016/j.drugalcdep.2014.12.005. PMC 4297708. PMID 25548026.
  5. ^ Forsyth AN (22 May 2012). "Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines". ScholarWorks@UNO. Retrieved 4 November 2024.
  6. ^ a b c d e Blough B (July 2008). "Dopamine-releasing agents" (PDF). In Trudell ML, Izenwasser S (eds.). Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. pp. 305–320. ISBN 978-0-470-11790-3. OCLC 181862653. OL 18589888W.
  7. ^ a b Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse. 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707. S2CID 15573624.
  8. ^ Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, Rothman RB, Goldberg SR, Lupica CR, Sitte HH, Brandt SD, Tella SR, Cozzi NV, Schindler CW (March 2013). "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology. 38 (4): 552–562. doi:10.1038/npp.2012.204. PMC 3572453. PMID 23072836.
  9. ^ a b c Partilla JS, Dersch CM, Baumann MH, Carroll FI, Rothman RB (1999). "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 (PDF). NIDA Res Monogr. Vol. 180. pp. 1–476 (252). PMID 11680410. 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. ^ Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, Brandt SD, Rothman RB, Ruoho AE, Cozzi NV (April 2012). "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology. 37 (5): 1192–1203. doi:10.1038/npp.2011.304. PMC 3306880. PMID 22169943.
  11. ^ a b "Phenylmorpholines and analogues thereof". Google Patents. 20 May 2011. Retrieved 7 December 2024.
  12. ^ a b c d e f g Rothman RB, Katsnelson M, Vu N, Partilla JS, Dersch CM, Blough BE, Baumann MH (June 2002). "Interaction of the anorectic medication, phendimetrazine, and its metabolites with monoamine transporters in rat brain". European Journal of Pharmacology. 447 (1): 51–57. doi:10.1016/s0014-2999(02)01830-7. PMID 12106802.
  13. ^ McLaughlin G, Baumann MH, Kavanagh PV, Morris N, Power JD, Dowling G, Twamley B, O'Brien J, Hessman G, Westphal F, Walther D, Brandt SD (September 2018). "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. doi:10.1002/dta.2396. PMC 7316143. PMID 29673128.
  14. ^ Rothman RB, Baumann MH (October 2003). "Monoamine transporters and psychostimulant drugs". European Journal of Pharmacology. 479 (1–3): 23–40. doi:10.1016/j.ejphar.2003.08.054. PMID 14612135.
  15. ^ Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry. 6 (17): 1845–1859. doi:10.2174/156802606778249766. PMID 17017961. Archived from the original on 26 March 2017. Retrieved 5 May 2020.
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