Orally Active Central Dopamine and Serotonin Receptor Ligands: 5-, 6-, 7-, and 8-[[(Trifluoromethyl)sulfonyl]oxy]-2-(di-n-propylamino)tetralins and the Formation of Active Metabolites in Vivo

The racemic triflate derivatives 5–8 of the 5-, 6-, 7-, and 8-hydroxylated 2-(di-n-propylamino)-tetralins 1–4 were shown to possess similar pharmacological profiles to their phenolic counterparts in in vitro binding and in vivo biochemical and behavioral assays in rats. Consequently, subcutaneous administration of the 5-, 6-, and 7-triflates displayed essentially dopaminergic agonist properties, while the 8-triflate was shown to be a selective 5-HT_1A receptor agonist. With respect to their agonist activities, the triflates were less potent than their phenolic analogs. The absolute oral bioavailability of compound 8 (8-triflate) was 4–5 times greater than the corresponding hydroxylated compound. Interestingly, in the in vivo biochemical assay compound 8 was found to be more potent after oral than after subcutaneous administration, indicating formation of one or more active metabolites. Following a study of the metabolism of compound 8 in rat hepatocytes, the monopropyl analog 9 was identified as the major metabolite and was suprisingly found to be more potent than compound 8. Oral administration of compound 5 (5-triflate) resulted in behavioral and biochemical effects indicative of mixed DA/5-HT_1A agonist properties not seen after subcutaneous administration. These results may also be indicative of the formation of active metabolites.