|Systematic (IUPAC) name|
|Mol. mass||237.339 g/mol|
Sertraline has been called "3,4-dichloro tametraline". This is correct but it is an oversimplification in the sense that sertraline is the SS 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] 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.
- Cis/Trans Ratio 1.1
- CAN radical induced dimerization of styrene 1.2
- Enantiopurified Trans- and Cis- Aminotetraline Derivatives 2.1
- Racemic Cis- and Trans- Aminotetraline Derivatives 2.2
- See also 3
- External links 4
- References 5
Two routes have been previously described, one for aryl moieties containing electron withdrawing groups, and one for electron donating groups:
Sarges, R. . (1975). "Synthesis of phenyl-substituted 1-aminotetralines". The Journal of Organic Chemistry 40 (9): 1216–1224.
"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."
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 (see also: CAN) cyclodimerization of various styrenes in acetonitrile and acrylonitrile is described."   doi:10.1021/ol0257934
Certain aromatic substitutients have a potentiating effect (e.g., p-Br), whereas others negate the compound's intrinsic activity.
Enantiopurified Trans- and Cis- Aminotetraline Derivatives
|Enantiopurified 4-aryl-aminotetralins IC50 (μM)|
Interestingly, (±)-sertraline is not entirely SERT selective until it has been resolved into the SS enantiomer.
In terms of the trans- isomers there is relatively marked separation in the activity between the RS and SR 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.
- CP-24,441 (1R, 4S-N-methyl- 4-phenyl-1,2,3,4-tetrahydro-1-naphthylamine)
- CP-39,332 (N-methyl-4-phenyl-1,2,3,4-tetrahydro-2- naphthylamine)
- Cyproheptadine [4-(5H-dibenz-[a,d]cyclohepten-5-ylidine)-1-methylpiperidine]
- EXP-561 (1-amino-4-phenylbicyclo[2.2.2]octane)
Sepracor has tried to patent the trans dichloro analog U.S. Patent 7,105,699.
During his 40 years at Pfizer, Koe authored more than 100 articles and papers. ... Koe learned to review previous studies and to build on findings that had failed to lead to successful products. In his early work with serotonin, for example, he studied the chemical tametraline, which proved ineffective as an anti-depressant.
Tests showed the chemical functioned more as a stimulant, a use Pfizer was not interested in pursuing. Although his research had failed to yield the desired result, Koe was convinced that the development of a viable anti-depressant was within reach.
- Koe, B. K.; Weissman, A.; Welch, W. M.; Browne, R. G. (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". The Journal of Pharmacology and Experimental Therapeutics 226 (3): 686–700.
- Koe, B. K. (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): 649–661.
- Sarges, R.; Koe, B. K.; Weissman, A.; Schaefer, J. P. (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.
- Welch, W. M.; Kraska, A. R.; Sarges, R.; Koe, B. K. (1984). "Nontricyclic antidepressant agents derived from cis- and trans-1-amino-4-aryltetralins". Journal of Medical Chemistry 27 (11): 1508–1515.