title: 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.
abstract: The racemic triflate derivatives 5-8 of the 5-, 6-, 7-, and 8-hydroxylated 2-(di-n-propylamino)-teralins 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-HT1A 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 surprisingly 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-HT1A agonist properties not seen after subcutaneous administration. These results may also be indicative of the formation of active metabolites.
authors.affiliation: Department of Pharmacology, Medicinaregatan, Göteborg, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Sonesson
authors.forename: M
authors.initials: M
authors.lastname: Boije
authors.forename: K
authors.initials: K
authors.lastname: Svensson
authors.forename: A
authors.initials: A
authors.lastname: Ekman
authors.forename: A
authors.initials: A
authors.lastname: Carlsson
authors.forename: A G
authors.initials: AG
authors.lastname: Romero
authors.forename: I J
authors.initials: IJ
authors.lastname: Martin
authors.forename: J N
authors.initials: JN
authors.lastname: Duncan
authors.forename: L J
authors.initials: LJ
authors.lastname: King
authors.forename: H
authors.initials: H
authors.lastname: Wikström
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001682:Biological Availability; D001711:Biotransformation; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D007275:Injections, Intravenous; D008024:Ligands; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D006845:Hydrocarbons, Fluorinated; D008024:Ligands; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D013764:Tetrahydronaphthalenes; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin