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{{Short description|Chemical compound}}
{{cs1 config|name-list-style=vanc}}
{{Drugbox
{{Drugbox
| Verifiedfields =
| Verifiedfields =
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<!-- Identifiers -->
<!-- Identifiers -->
| CAS_number_Ref =
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 75240-91-4
| CAS_number = 75240-91-4
| CAS_supplemental = <br />85966-89-8 ((+)-[[enantiomer|isomer]])
| CAS_supplemental = <br />85966-89-8 ((+)-[[enantiomer|isomer]])
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| ChemSpiderID_Ref =
| ChemSpiderID_Ref =
| ChemSpiderID = 50067
| ChemSpiderID = 50067
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII =
| UNII = ND3NDM2EHM
| KEGG =
| KEGG =
| ChEBI = 125440
| ChEBI = 125440
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<!--Chemical data-->
<!--Chemical data-->
| C=14 | H=21 | N=1 | O=1
| C=14 | H=21 | N=1 | O=1
| molecular_weight = 219.328 g/mol
| SMILES = CCCN1CCCC(C1)C2=CC(=CC=C2)O
| SMILES = CCCN1CCCC(C1)C2=CC(=CC=C2)O
| StdInChI_Ref =
| StdInChI_Ref =
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}}
}}


'''3-PPP''' ('''''N''-''n''-propyl-3-(3-hydroxyphenyl)piperidine''') is a mixed [[sigma receptor|sigma]] [[sigma-1 receptor|σ<sub>1</sub>]] and [[sigma-2 receptor|σ<sub>2</sub> receptor]] [[agonist]] (with similar [[affinity (pharmacology)|affinity]] for both subtypes, though slightly higher affinity for the latter)<ref name="pmid2174717">{{cite journal | vauthors = Hellewell SB, Bowen WD | title = A sigma-like binding site in rat pheochromocytoma (PC12) cells: decreased affinity for (+)-benzomorphans and lower molecular weight suggest a different sigma receptor form from that of guinea pig brain | journal = Brain Res. | volume = 527 | issue = 2 | pages = 244–53 | year = 1990 | pmid = 2174717 | doi = | url = }}</ref> and [[D2 receptor|D<sub>2</sub> receptor]] [[partial agonist]] which is used in [[scientific research]].<ref name="pmid6415751">{{cite journal | vauthors = Hjorth S, Carlsson A, Clark D, Svensson K, Wikström H, Sanchez D, Lindberg P, Hacksell U, Arvidsson LE, Johansson A | title = Central dopamine receptor agonist and antagonist actions of the enantiomers of 3-PPP | journal = Psychopharmacology | volume = 81 | issue = 2 | pages = 89–99 | year = 1983 | pmid = 6415751 | doi = | url = }}</ref><ref name="pmid7925616">{{cite journal | vauthors = Hellewell SB, Bruce A, Feinstein G, Orringer J, Williams W, Bowen WD | title = Rat liver and kidney contain high densities of sigma 1 and sigma 2 receptors: characterization by ligand binding and photoaffinity labeling | journal = Eur. J. Pharmacol. | volume = 268 | issue = 1 | pages = 9–18 | year = 1994 | pmid = 7925616 | doi = | url = }}</ref> It shows [[stereoselectivity]] in its [[pharmacodynamics]].<ref name="pmid6415751" /> (+)-3-PPP is the [[enantiomer]] that acts as an agonist of the sigma receptors;<ref name="pmid7925616" /> it is also an agonist of both D<sub>2</sub> [[presynaptic]] and [[postsynaptic receptor]]s.<ref name="pmid6415751" /> Conversely, (–)-3-PPP, also known as '''preclamol''' ({{abbrlink|INN|International Nonproprietary Name}}), acts as an agonist of presynaptic D<sub>2</sub> receptors but as an antagonist of postsynaptic D<sub>2</sub> receptors, and has [[antipsychotic]] effects.<ref name="pmid6415751" /><ref name="Albert2012">{{cite book|author=Jeffrey S. Albert|title=Targets and Emerging Therapies for Schizophrenia|url=https://books.google.com/books?id=L1Xnqh2GOdAC&pg=PT64|date=6 June 2012|publisher=John Wiley & Sons|isbn=978-1-118-30940-7|pages=64–}}</ref> 3-PPP has also been reported to be a [[monoamine reuptake inhibitor]] and possibly to act at [[adrenergic receptor]]s or some other non-sigma receptor.<ref name="AcademicPress1993">{{cite book|title=Annual Reports in Medicinal Chemistry|url=https://books.google.com/books?id=648kNU6aMMYC&pg=PR14|date=5 October 1993|publisher=Academic Press|isbn=978-0-08-058372-3|pages=14–}}</ref>
'''3-PPP''' ('''''N''-''n''-propyl-3-(3-hydroxyphenyl)piperidine''') is a mixed [[sigma receptor|sigma]] [[sigma-1 receptor|σ<sub>1</sub>]] and [[sigma-2 receptor|σ<sub>2</sub> receptor]] [[agonist]] (with similar [[affinity (pharmacology)|affinity]] for both subtypes, though slightly higher affinity for the latter)<ref name="pmid2174717">{{cite journal | vauthors = Hellewell SB, Bowen WD | title = A sigma-like binding site in rat pheochromocytoma (PC12) cells: decreased affinity for (+)-benzomorphans and lower molecular weight suggest a different sigma receptor form from that of guinea pig brain | journal = Brain Res. | volume = 527 | issue = 2 | pages = 244–253 | year = 1990 | pmid = 2174717 | doi = 10.1016/0006-8993(90)91143-5| s2cid = 24546226 }}</ref> and [[D2 receptor|D<sub>2</sub> receptor]] [[partial agonist]] which is used in [[scientific research]].<ref name="pmid6415751">{{cite journal | vauthors = Hjorth S, Carlsson A, Clark D, Svensson K, Wikström H, Sanchez D, Lindberg P, Hacksell U, Arvidsson LE, Johansson A | title = Central dopamine receptor agonist and antagonist actions of the enantiomers of 3-PPP | journal = Psychopharmacology | volume = 81 | issue = 2 | pages = 89–99 | year = 1983 | pmid = 6415751 | doi = 10.1007/bf00428999| s2cid = 1168359 }}</ref><ref name="pmid7925616">{{cite journal | vauthors = Hellewell SB, Bruce A, Feinstein G, Orringer J, Williams W, Bowen WD | title = Rat liver and kidney contain high densities of sigma 1 and sigma 2 receptors: characterization by ligand binding and photoaffinity labeling | journal = Eur. J. Pharmacol. | volume = 268 | issue = 1 | pages = 9–18 | year = 1994 | pmid = 7925616 | doi = 10.1016/0922-4106(94)90115-5}}</ref> It shows [[stereoselectivity]] in its [[pharmacodynamics]].<ref name="pmid6415751" /> (+)-3-PPP is the [[enantiomer]] that acts as an agonist of the sigma receptors;<ref name="pmid7925616" /> it is also an agonist of both D<sub>2</sub> [[presynaptic]] and [[postsynaptic receptor]]s.<ref name="pmid6415751" /> Conversely, (−)-3-PPP, also known as '''preclamol''' ({{abbrlink|INN|International Nonproprietary Name}}), acts as an agonist of presynaptic D<sub>2</sub> receptors but as an antagonist of postsynaptic D<sub>2</sub> receptors, and has [[antipsychotic]] effects.<ref name="pmid6415751" /><ref name="Albert2012">{{cite book|author=Jeffrey S. Albert|title=Targets and Emerging Therapies for Schizophrenia|url=https://books.google.com/books?id=L1Xnqh2GOdAC&pg=PT64|date=6 June 2012|publisher=John Wiley & Sons|isbn=978-1-118-30940-7|pages=64–}}</ref> 3-PPP has also been reported to be a [[monoamine reuptake inhibitor]] and possibly to act at [[adrenergic receptor]]s or some other non-sigma receptor.<ref name="AcademicPress1993">{{cite book|title=Annual Reports in Medicinal Chemistry|url=https://books.google.com/books?id=648kNU6aMMYC&pg=PR14|date=5 October 1993|publisher=Academic Press|isbn=978-0-08-058372-3|pages=14–}}</ref>
==Synthesis==

[[File:Preclamol synthesis.svg|center|500px|thumb|[https://www.chemdrug.com/article/8/3284/16419541.html ChemDrug] Synthesis:<ref>Serradell, MN; Nohria, V.; Castaer, J.; Blancafort, P.; 3-PPP. Drugs Fut 1983, 8, 1, 27.</ref><ref>Hacksell, Uli; Arvidsson, Lars Erik; Svensson, Uno; Nilsson, J. Lars G.; Sanchez, Domingo; Wikstroem, Hakan; Lindberg, Per; Hjorth, Stephan; Carlsson, Arvid (1981). "3-Phenylpiperidines. Central dopamine-autoreceptor stimulating activity". Journal of Medicinal Chemistry. 24 (12): 1475–1482. doi:10.1021/jm00144a021.</ref><ref>Thorberg, Seth-Olov; Gawell, Lars; Csöregh, Ingeborg; Nilsson, J.L.G. (1985). "Large scale synthesis and absolute configuration of (-)-3-ppp, a selective dopamine autoreceptor agonist". Tetrahedron. 41 (1): 129–139. doi:10.1016/S0040-4020(01)83477-3.</ref> Patent:<ref>P Carlsson, et al. WO1981001552 (to Dr Per Arvid Emil Carlsson Te Gotenburg Zweden).</ref> Short & Efficient:<ref>Filippis, Arnault; Pardo, Domingo; Cossy, Janine (2005). "A Very Short and Efficient Synthesis of Preclamol". Letters in Organic Chemistry 2 (2): 136–138. doi:10.2174/1570178053202883.</ref> Sino:<ref>王敏, et al. CN109232386 (2019 to China Agricultural University).</ref>]]
The Grignard reagent was prepared for 3-Bromoanisole [2398-37-0] (1) and this was reacted with 3-Bromopyridine [626-55-1] (2) to give 3-(3-methoxyphenyl)pyridine [4373-67-5] (3). Reaction with 1-bromopropane [106-94-5] occurred to give the quaternary salt PC13695099 (4a). {Alternatively catalytic hydrogenation of 3 could be attempted directly to give 3-(3-methoxyphenyl)piperidine [79601-21-1] (4b). A second reductive amination with propionic acid was then performed.} Catalytic hydrogenation of the quat cation gave 3-(3-methoxyphenyl)-1-propylpiperidine [86562-23-4] (5). Demethylation with hydrogen bromide then completed the synthesis of preclamol (6).
==See also==
==See also==
* [[4-PPBP]]
* [[4-PPBP]]
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* [[OSU-6162]]
* [[OSU-6162]]
* [[PF-219,061]]
* [[PF-219,061]]
* [[Myfadol]]


==References==
==References==
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[[Category:Piperidines]]
[[Category:Piperidines]]
[[Category:Sigma agonists]]
[[Category:Sigma agonists]]



{{Nervous-system-drug-stub}}
{{Nervous-system-drug-stub}}

Latest revision as of 12:28, 14 June 2024

3-PPP
Clinical data
Other namesPreclamol
Identifiers
  • (±)-3-(1-Propylpiperidin-3-yl)phenol
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC14H21NO
Molar mass219.328 g·mol−1
3D model (JSmol)
  • CCCN1CCCC(C1)C2=CC(=CC=C2)O
  • InChI=1S/C14H21NO/c1-2-8-15-9-4-6-13(11-15)12-5-3-7-14(16)10-12/h3,5,7,10,13,16H,2,4,6,8-9,11H2,1H3
  • Key:HTSNFXAICLXZMA-UHFFFAOYSA-N

3-PPP (N-n-propyl-3-(3-hydroxyphenyl)piperidine) is a mixed sigma σ1 and σ2 receptor agonist (with similar affinity for both subtypes, though slightly higher affinity for the latter)[1] and D2 receptor partial agonist which is used in scientific research.[2][3] It shows stereoselectivity in its pharmacodynamics.[2] (+)-3-PPP is the enantiomer that acts as an agonist of the sigma receptors;[3] it is also an agonist of both D2 presynaptic and postsynaptic receptors.[2] Conversely, (−)-3-PPP, also known as preclamol (INNTooltip International Nonproprietary Name), acts as an agonist of presynaptic D2 receptors but as an antagonist of postsynaptic D2 receptors, and has antipsychotic effects.[2][4] 3-PPP has also been reported to be a monoamine reuptake inhibitor and possibly to act at adrenergic receptors or some other non-sigma receptor.[5]

Synthesis

[edit]
ChemDrug Synthesis:[6][7][8] Patent:[9] Short & Efficient:[10] Sino:[11]

The Grignard reagent was prepared for 3-Bromoanisole [2398-37-0] (1) and this was reacted with 3-Bromopyridine [626-55-1] (2) to give 3-(3-methoxyphenyl)pyridine [4373-67-5] (3). Reaction with 1-bromopropane [106-94-5] occurred to give the quaternary salt PC13695099 (4a). {Alternatively catalytic hydrogenation of 3 could be attempted directly to give 3-(3-methoxyphenyl)piperidine [79601-21-1] (4b). A second reductive amination with propionic acid was then performed.} Catalytic hydrogenation of the quat cation gave 3-(3-methoxyphenyl)-1-propylpiperidine [86562-23-4] (5). Demethylation with hydrogen bromide then completed the synthesis of preclamol (6).

See also

[edit]

References

[edit]
  1. ^ Hellewell SB, Bowen WD (1990). "A sigma-like binding site in rat pheochromocytoma (PC12) cells: decreased affinity for (+)-benzomorphans and lower molecular weight suggest a different sigma receptor form from that of guinea pig brain". Brain Res. 527 (2): 244–253. doi:10.1016/0006-8993(90)91143-5. PMID 2174717. S2CID 24546226.
  2. ^ a b c d Hjorth S, Carlsson A, Clark D, Svensson K, Wikström H, Sanchez D, Lindberg P, Hacksell U, Arvidsson LE, Johansson A (1983). "Central dopamine receptor agonist and antagonist actions of the enantiomers of 3-PPP". Psychopharmacology. 81 (2): 89–99. doi:10.1007/bf00428999. PMID 6415751. S2CID 1168359.
  3. ^ a b Hellewell SB, Bruce A, Feinstein G, Orringer J, Williams W, Bowen WD (1994). "Rat liver and kidney contain high densities of sigma 1 and sigma 2 receptors: characterization by ligand binding and photoaffinity labeling". Eur. J. Pharmacol. 268 (1): 9–18. doi:10.1016/0922-4106(94)90115-5. PMID 7925616.
  4. ^ Jeffrey S. Albert (6 June 2012). Targets and Emerging Therapies for Schizophrenia. John Wiley & Sons. pp. 64–. ISBN 978-1-118-30940-7.
  5. ^ Annual Reports in Medicinal Chemistry. Academic Press. 5 October 1993. pp. 14–. ISBN 978-0-08-058372-3.
  6. ^ Serradell, MN; Nohria, V.; Castaer, J.; Blancafort, P.; 3-PPP. Drugs Fut 1983, 8, 1, 27.
  7. ^ Hacksell, Uli; Arvidsson, Lars Erik; Svensson, Uno; Nilsson, J. Lars G.; Sanchez, Domingo; Wikstroem, Hakan; Lindberg, Per; Hjorth, Stephan; Carlsson, Arvid (1981). "3-Phenylpiperidines. Central dopamine-autoreceptor stimulating activity". Journal of Medicinal Chemistry. 24 (12): 1475–1482. doi:10.1021/jm00144a021.
  8. ^ Thorberg, Seth-Olov; Gawell, Lars; Csöregh, Ingeborg; Nilsson, J.L.G. (1985). "Large scale synthesis and absolute configuration of (-)-3-ppp, a selective dopamine autoreceptor agonist". Tetrahedron. 41 (1): 129–139. doi:10.1016/S0040-4020(01)83477-3.
  9. ^ P Carlsson, et al. WO1981001552 (to Dr Per Arvid Emil Carlsson Te Gotenburg Zweden).
  10. ^ Filippis, Arnault; Pardo, Domingo; Cossy, Janine (2005). "A Very Short and Efficient Synthesis of Preclamol". Letters in Organic Chemistry 2 (2): 136–138. doi:10.2174/1570178053202883.
  11. ^ 王敏, et al. CN109232386 (2019 to China Agricultural University).
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