2-Phenylmorpholine

2-Phenylmorpholine
Clinical data
Other names	PAL-632; PAL632
Drug class	Norepinephrine–dopamine releasing agent; Psychostimulant
Identifiers
	IUPAC name 2-phenylmorpholine;
CAS Number	23972-41-0 ;
PubChem CID	91101;
ChemSpider	82261;
ChEMBL	ChEMBL4069068;
CompTox Dashboard (EPA)	DTXSID70946825 ;
Chemical and physical data
Formula	C10H13NO
Molar mass	163.220 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C1COC(CN1)C2=CC=CC=C2;
	InChI InChI=1S/C10H13NO/c1-2-4-9(5-3-1)10-8-11-6-7-12-10/h1-5,10-11H,6-8H2; Key:ZLNGFYDJXZZFJP-UHFFFAOYSA-N;

2-Phenylmorpholine (code name PAL-632) is the parent compound of the substituted phenylmorpholine class of compounds.^[1] Examples of 2-phenylmorpholine derivatives (i.e., substituted phenylmorpholines) include phenmetrazine (3-methyl-2-phenylmorpholine), phendimetrazine ((2S,3S)-3,4-dimethyl-2-phenylmorpholine), and pseudophenmetrazine ((2RS,3SR)-3-methyl-2-phenylmorpholine), which are monoamine releasing agents (MRAs) and psychostimulants.^[1]^[2]^[3]^[4] 2-Phenylmorpholine itself is a potent norepinephrine–dopamine releasing agent (NDRA) and hence may act as a stimulant similarly.^[5]

Monoamine release of 2-phenylmorpholine 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	^[6]^[7]^[8]
Dextroamphetamine	6.6–10.2	5.8–24.8	698–1,765	^[9]^[10]^[8]^[11]
Dextromethamphetamine	12.3–14.3	8.5–40.4	736–1,292	^[9]^[12]^[8]^[11]
2-Phenylmorpholine	79	86	20,260	^[5]
Phenmetrazine	29–50.4	70–131	7,765–>10,000	^[4]^[8]^[13]^[5]
Phendimetrazine	>10,000	>10,000	>100,000	^[4]^[8]^[11]
Pseudophenmetrazine	514	>10,000 (RI)	>10,000	^[4]
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: ^[2]^[3]

References

^ ^a ^b Meher CP, Purohit D, Kumar A, Singh R, Dubey A (13 April 2022). "An Updated Review on Morpholine Derivatives With Their Pharmacological Actions". International Journal of Health Sciences: 2218–2249. doi:10.53730/ijhs.v6nS3.5983. ISSN 2550-696X. Retrieved 10 January 2025.
^ ^a ^b 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.
^ ^a ^b 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.
^ ^a ^b ^c ^d Rothman RB, Katsnelson M, Vu N, Partilla JS, Dersch CM, Blough BE, 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): 51–57. doi:10.1016/s0014-2999(02)01830-7. PMID 12106802.
^ ^a ^b ^c "Phenylmorpholines and analogues thereof". Google Patents. 20 May 2011. Retrieved 7 December 2024.
^ Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, et al. (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.
^ Forsyth AN (22 May 2012). "Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines". ScholarWorks@UNO. Retrieved 4 November 2024.
^ ^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.
^ ^a ^b Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, et al. (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.
^ Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, et al. (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.
^ ^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. Archived from the original (PDF) on August 5, 2023. 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.
^ Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, et al. (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.
^ McLaughlin G, Baumann MH, Kavanagh PV, Morris N, Power JD, Dowling G, et al. (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.

This psychoactive drug-related article is a stub. You can help Wikipedia by expanding it.

[MeherPurohitKumar2022-1] Meher CP, Purohit D, Kumar A, Singh R, Dubey A (13 April 2022). "An Updated Review on Morpholine Derivatives With Their Pharmacological Actions". International Journal of Health Sciences: 2218–2249. doi:10.53730/ijhs.v6nS3.5983. ISSN 2550-696X. Retrieved 10 January 2025.

[RothmanBaumann2003-2] 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.

[RothmanBaumann2006-3] 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.

[RothmanKatsnelsonVu2002-4] Rothman RB, Katsnelson M, Vu N, Partilla JS, Dersch CM, Blough BE, 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): 51–57. doi:10.1016/s0014-2999(02)01830-7. PMID 12106802.

[WO2011146850A1-5] "Phenylmorpholines and analogues thereof". Google Patents. 20 May 2011. Retrieved 7 December 2024.

[ReithBloughHong2015-6] Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, et al. (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.

[Forsyth2012-7] Forsyth AN (22 May 2012). "Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines". ScholarWorks@UNO. Retrieved 4 November 2024.

[Blough2008-8] 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.

[RothmanBaumannDersch2001-9] Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, et al. (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.

[BaumannPartillaLehner2013-10] Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, et al. (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.

[PartillaDerschBaumann1999-11] 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. Archived from the original (PDF) on August 5, 2023. 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.

[BaumannAyestasPartilla2012-12] Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, et al. (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.

[McLaughlinBaumannKavanagh2018-13] McLaughlin G, Baumann MH, Kavanagh PV, Morris N, Power JD, Dowling G, et al. (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.

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2-Phenylmorpholine

References

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