SYNTHESIS OF -3-N,N-DIMETHYLAMINO-1,2,3,4-TETRAHYDRONAPHTHALENE (H-2-PAT)

Subsequent to the discovery that the (+)-benzomorphan sigma receptor l igands, (+)-pentazocine and (+)-N-allylnormetazocine, stimulated tyros ine hydroxylase activity and dopamine synthesis in rat striatum in vit ro, we reported a similar effect on a structurally similar series of 1 -phenyl-3-aminoeetrahydronaphthalenes (phenylaminotetralins, PAT's). B oth racemic -phenyl-3-dimethylamino-6-chloro-7-hydroxytetralin (Cl,OH- PAT) and racemic 1-phenyl-3-dimethylaminotetralin (H-2-PAT) stimulated tyrosine hydroxylase with an EC(50) of approximately 0.1 mu M. The fo rmer was also found to have a non-specific dopamine releasing effect w hile the latter was devoid of such activity affording it the less comp licated pharmacological profile of the two analogs. We previously repo rted the synthesis of tritium labeled CI,OH-PAT to be used in radiorec eptor and autoradiography studies and found that it labeled a sigma-li ke site in guinea pig brain with an apparent Kd of similar to 50 pM an d with a pharmacological profile unique from other known CNS receptors . Here we report the synthesis of high specific activity tritium label ed trans-(1R,3S)-(-)H-2-PAT as this enantiomer was found to be more ac tive in the tyrosine hydroxylase assay and possessed approximately 45 fold greater affinity for the novel neuromodulatory sigma-like recepto r.