ORALLY-ACTIVE CENTRAL DOPAMINE AND SEROTONIN RECEPTOR LIGANDS - ETHYL)SULFONYL]OXY]-2-(DI-N-PROPYLAMINO)TETRALINS, ETHYL)SULFONYL]OXY]-2-(DI-N-PROPYLAMINO)TETRALINS, ETHYL)SULFONYL]OXY]-2-(DI-N-PROPYLAMINO)TETRALINS, AND METHYL)SULFONYL]OXY]-2-(DI-N-PROPYLAMINO)TETRALINS AND THEFORMATION OF ACTIVE METABOLITES IN-VIVO

The racemic triflate derivatives 5-8 of the 5-, 6-, 7-, and 8-hydroxyl ated 2-(di-n-propylamino)-tetralins 1-4 were shown to possess similar pharmacological profiles to their phenolic counterparts in in vitro bi nding and in vivo biochemical and behavioral assays in rats. Consequen tly, subcutaneous administration of the 5-, 6-, and 7-triflates displa yed essentially dopaminergic agonist properties, while the 8-triflate was shown to be a selective 5-HT1A receptor agonist. With respect to t heir agonist activities, the triflates were less potent than their phe nolic analogs. The absolute oral bioavailability of compound 8 (8-trif late) was 4-5 times greater than the corresponding hydroxylated compou nd. Interestingly, in the in vivo biochemical assay compound 8 was fou nd 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 monoprop yl analog 9 was identified as the major metabolite and was suprisingly found to be more potent than compound 8. Oral administration of compo und 5 (5-triflate) resulted in behavioral and biochemical effects indi cative of mixed DA/5-HT1A agonist properties not seen after subcutaneo us administration. These results may also be indicative of the formati on of active metabolites.