title: Synthesis and evaluation of pharmacological and pharmacokinetic properties of monopropyl analogs of 5-, 7-, and 8-[[(trifluoromethyl)sulfonyl]oxy]-2-aminotetralins: central dopamine and serotonin receptor activity.
abstract: In order to explore further the structure-activity relationships of serotonergic and dopaminergic ligands, a series of enantiopure 5-, 7-, or 8-triflate (-OTf)-substituted 2-(monopropylamino)-tetralins have been synthesized and evaluated in in vitro binding and in vivo biochemical and behavioral assays in rats. Consequently, the 8-OTf-substituted compound R-(+)-6 was found to be a potent and selective 5-HT1A (5-hydroxytryptamine) receptor agonist inducing a full-blown 5-HT syndrome in normal rats, while the corresponding 5-OTf-substituted compound S-(-)-12 was found to be a preferential dopamine (DA) autoreceptor agonist. A partial 5-HT syndrome was also observed for S-(-)-12, while the corresponding R-(+)-12 was found to be inactive at the DA and 5-HT receptors both in vitro and in vivo. Compounds 6 and 12 were found to be major urinary metabolites following oral administration of their dipropyl analogs (2 and 13, respectively). Thus 6 was proposed to be the metabolite responsible for the full-blown 5-HT syndrome seen after oral (but not subcutaneous) administration of 2. Similarly, 12 was proposed to be the metabolite responsible for the partial 5-HT syndrome seen after oral (but not subcutaneous) administration of 13. The bioavailability of R-(+)-6 (7.6 +/- 1.1%) appeared to be slightly lower than that of 2 (11.2 +/- 5.2%), although the in vitro metabolism of R-(+)-6 appeared to be slower than that of 2. Therefore first-pass metabolism was not thought to be the reason for the lower bioavailability of R-(+)-6, as compared to 2.
authors.affiliation: Department of Pharmacology, University of Göteborg, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Sonesson
authors.forename: T
authors.initials: T
authors.lastname: Barf
authors.forename: J
authors.initials: J
authors.lastname: Nilsson
authors.forename: D
authors.initials: D
authors.lastname: Dijkstra
authors.forename: A
authors.initials: A
authors.lastname: Carlsson
authors.forename: K
authors.initials: K
authors.lastname: Svensson
authors.forename: M W
authors.initials: MW
authors.lastname: Smith
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
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001682:Biological Availability; D002478:Cells, Cultured; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects*; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D013764:Tetrahydronaphthalenes