3-PPP

3-PPP
Clinical data
Other names	Preclamol
Identifiers
	IUPAC name (±)-3-(1-Propylpiperidin-3-yl)phenol;
CAS Number	75240-91-4 ; 85966-89-8 ((+)-isomer);
PubChem CID	55445;
ChemSpider	50067;
UNII	ND3NDM2EHM;
ChEBI	CHEBI:125440;
ChEMBL	ChEMBL276500;
CompTox Dashboard (EPA)	DTXSID7048453 ;
Chemical and physical data
Formula	C14H21NO
Molar mass	219.328 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CCCN1CCCC(C1)C2=CC(=CC=C2)O;
	InChI 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

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).

References

^ 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.
^ ^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.
^ ^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.
^ Jeffrey S. Albert (6 June 2012). Targets and Emerging Therapies for Schizophrenia. John Wiley & Sons. pp. 64–. ISBN 978-1-118-30940-7.
^ Annual Reports in Medicinal Chemistry. Academic Press. 5 October 1993. pp. 14–. ISBN 978-0-08-058372-3.
^ Serradell, MN; Nohria, V.; Castaer, J.; Blancafort, P.; 3-PPP. Drugs Fut 1983, 8, 1, 27.
^ 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.
^ 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.
^ P Carlsson, et al. WO1981001552 (to Dr Per Arvid Emil Carlsson Te Gotenburg Zweden).
^ 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.
^ 王敏, et al. CN109232386 (2019 to China Agricultural University).

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[pmid2174717-1] 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.

[pmid6415751-2] 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.

[pmid7925616-3] 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.

[Albert2012-4] Jeffrey S. Albert (6 June 2012). Targets and Emerging Therapies for Schizophrenia. John Wiley & Sons. pp. 64–. ISBN 978-1-118-30940-7.

[AcademicPress1993-5] 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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3-PPP

Synthesis

See also

References