Resolved cis- and trans-2-amino-5-methoxy-1-methyltetralins: Central dopamine receptor agonists and antagonists

Article abstract of DOI:10.1021/jm00387a004

A series of 35 stereochemically well-defined C₁-methyl-substituted derivatives of the potent dopamine (DA) receptor agonist 5-hydroxy-2-(di-n-propylamino)tetralin (5-OH-DPAT) have been synthesized. The compounds were tested for central DA receptor agonistic and antagonistic activity, by use of biochemical and behavioral tests in rats. In addition, the compounds were tested for in vivo interactions with 5,6-dihydroxy-2-(di-n-propylamino)tetralin (DiPr-5,6-ADTN). On the basis of pharmacological activity profiles, the active compounds have been classified into four groups: (a) classical pre- and postsynaptic DA receptor agonists, (b) DA receptor agonists with preferential action at presynaptic receptors, (c) pre- and postsynaptic DA receptor antagonists, and (d) DA receptor antagonists with preferential action at presynaptic receptors. Results obtained indicate that both 2R and 2S enantiomers of C₅-oxygenated 2-aminotetralins may be able to bind to DA receptors but that only 2S antipodes are able to activate the receptors. O-Methylation of the C₅-oxygenated (1S,2R)-2-amino-1-methyltetralin derivatives tends to increase their DA receptor antagonistic activity, whereas decrease of the size of the N-substituent(s) from n-propyl to ethyl or methyl appears to increase their activity at postsynaptic DA receptors.