Tametraline

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).

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, reverses reserpine induced hypothermia in mice, and blocks uptake of 3H-Norepinephrine into rat heart.

Tametraline is a norepinephrine-dopamine reuptake inhibitor.

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

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

"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."

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

See also .

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

CAN radical induced dimerization of styrene
"A facile one-pot synthesis of 1-amino-4-aryl-tetralin derivatives by the CAN-induced cyclodimerization of various styrenes in acetonitrile and acrylonitrile is described."

Structure-activity relationship
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

(±)-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

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

See also
 Cyproheptadine [4-(5H-dibenz-[a,d]cyclohepten-5-ylidine)-1-methylpiperidine]
 Dasotraline
 Desmethylsertraline
 EXP-561 (1-amino-4-phenylbicyclo[2.2.2]octane)
 JNJ-7925476
 Lometraline
 Nefopam
 Sertraline

References

Category:Amines
Category:Norepinephrine-dopamine reuptake inhibitors
Category:Pfizer brands
Category:Stimulants
Category:Tetralins