Tametraline

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Tametraline
Tametraline.svg
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Chemical and physical data
FormulaC17H19N
Molar mass237.339 g/mol g·mol−1
3D model (JSmol)
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Tametraline (CP-24,441) is the parent of a series of chemical compounds investigated at Pfizer that eventually led to the development of sertraline (CP-51,974-1).[1]

Sertraline has been called "3,4-dichloro-tametraline". This is correct but it is an oversimplification in the sense that sertraline is the S,S-isomer whereas tametraline is the 1R,4S-stereoisomer.

1R-Methylamino-4S-phenyl-tetralin is a potent inhibitor of norepinephrine uptake in rat brain synaptosomes,[2] reverses reserpine induced hypothermia in mice, and blocks uptake of 3H-Norepinephrine into rat heart.[3]

Tametraline is a norepinephrine-dopamine reuptake inhibitor.[4]

Indatraline is an indanamine homolog of tetralin-based tametraline, although in the case of indatraline the product is pm-dichlorinated.

Chemistry[edit]

Two routes have been previously described,[5] one for aryl moieties containing electron withdrawing groups, and one for electron donating groups:

Preparation of Tametraline: U.S. Patent 4,045,488 Reinhard Sarges; Pfizer Inc.

Sarges, R. . (1975). "Synthesis of phenyl-substituted 1-aminotetralines". The Journal of Organic Chemistry. 40 (9): 1216–1224. doi:10.1021/jo00897a008.

"As expected, Friedel-Crafts cyclization of the diarylbutyric acid derivatives # to the most reactive ring was observed with little or none of the alternative isomer being detected."

Tametraline synthesis.png

"The KMnO4 oxidation of the 1-aryl-tetralins # was observed to give 4-hydroxy-4-aryltetralones # instead of the expected tetralone # previously reported.[5] As a result of this finding, direct oxidation of Grignard reaction product # was attempted and found to be a more efficient route."

See also: U.S. Patent 4,045,488 (and refs therein: doi:10.1021/ja01193a020 doi:10.1021/ja01183a058 doi:10.1021/ja01157a130 doi:10.1021/ja01635a052)

cis-/trans-Ratio[edit]

In the case of 3,4-dichloro product, approximately 50:50 cis-/trans- ratio was achieved, according to the reference.[4]

CAN radical induced dimerization of styrene[edit]

"A facile one-pot synthesis of 1-amino-4-aryl-tetralin derivatives by the CAN-induced (see also: CAN) cyclodimerization of various styrenes in acetonitrile and acrylonitrile is described." [1] [2] doi:10.1021/ol0257934

one-pot synthesis of 1-amino-4-aryl-tetralin derivatives by the CAN-induced cyclodimerization of various styrenes in acetonitrile and acrylonitrile

Structure-activity relationship[edit]

Certain aromatic substitutients have a potentiating effect (e.g., p-Br), whereas others negate the compound's intrinsic activity.

It is not right to think of the dimethyl analogs as a "prodrug" to the monomethylated drugs (cf. indatraline, "31,345"), but it is correct that it is a "latentiated" form of the drug. This word is from the salsalate page. This was the reason why sertraline was made only as monomethylated because apparently according to the orders the 1° amine is inactive therefore the drug would have a shorter duration of activity.

Enantiopurified trans- and cis-aminotetraline derivatives[edit]

"31,345" structure:[6]
Enantiopurified 4-aryl-aminotetralins IC50 (μM)
Stereo X Y NE DA 5-HT
RS H H 0.018 0.15 0.84
SR H H 0.37 1.40 14.00
RS Cl H 0.019 0.052 0.084
SR Cl H 0.46 1.40 3.50
RS Cl Cl 0.01 0.044 0.039
SR Cl Cl 0.044 0.27 0.47
SS Cl Cl 1.20 1.30 0.06
RR Cl Cl 0.30 0.32 0.46

(±)-sertraline is not entirely SERT selective until it has been resolved into the S,S-enantiomer.

In terms of the trans- isomers there is relatively marked separation in the activity between the R,S- and S,R-enantiomers. This stands in contrast to what has been observed in the homologous indamine class where both of the trans- enantiomers possessed significant TRI activity at all three of the monoamine transporters.

Racemic cis- and trans-aminotetraline derivatives[edit]

The primary amines are claimed to completely lack any affinity for the transporters.

See also[edit]

References[edit]

  1. ^ Koe, BK; Weissman, A; Welch, WM; Browne, RG (September 1983). "Sertraline, 1S,4S-N-Methyl-4-(3,4-Dichlorophenyl)-1,2,3,4-Tetrahydro-1-Naphthylamine, a New Uptake Inhibitor with Selectivity for Serotonin" (PDF). The Journal of Pharmacology and Experimental Therapeutics. 226 (3): 686–700. PMID 6310078. Retrieved 10 August 2016.
  2. ^ Koe, BK (December 1976). "Molecular Geometry of Inhibitors of the Uptake of Catecholamines and Serotonin in Synaptosomal Preparations of Rat Brain". The Journal of Pharmacology and Experimental Therapeutics. 199 (3): 649–61. PMID 994022.
  3. ^ Sarges, R; Koe, BK; Weissman, A; Schaefer, JP (December 1974). "Blockade of Heart 3H-Norepinephrine Up-take by 4-Phenyl-1-Aminotetralines: Implications for the Active Conformation of Imipramine-Like Drugs". The Journal of Pharmacology and Experimental Therapeutics. 191 (3): 393–402. PMID 4427286.
  4. ^ a b Welch, WM; Kraska, AR; Sarges, R; Koe, BK (November 1984). "Nontricyclic Antidepressant Agents Derived from cis- and trans-1-Amino-4-aryltetralins". Journal of Medicinal Chemistry. 27 (11): 1508–15. doi:10.1021/jm00377a021. PMID 6492080.
  5. ^ a b Sarges, RA (May 1975). "Synthesis of Phenyl-Substituted 1-Aminotetralines". The Journal of Organic Chemistry. 40 (9): 1216–24. doi:10.1021/jo00897a008.
  6. ^ Peng, XQ; Xi, ZX; Li, X; Spiller, K; Li, J; Chun, L; Wu, KM; Froimowitz, M; Gardner, EL (December 2010). "Is Slow-Onset Long-Acting Monoamine Transport Blockade to Cocaine as Methadone is to Heroin? Implication for Anti-Addiction Medications". Neuropsychopharmacology. 35 (13): 2564–78. doi:10.1038/npp.2010.133. PMC 2978747. PMID 20827272.