title: Pharmacology of the novel 5-hydroxytryptamine1A receptor antagonist (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin: inhibition of (R)-8-hydroxy-2-(dipropylamino)tetralin-induced effects.
abstract: The selective 5-hydroxytryptamine (5-HT1A) receptor agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) induces a large number of pharmacological effects. In the present study we demonstrate that a novel 8-OH-DPAT analog, (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin [(S)-UH-301], is able to antagonize completely the following (R)-8-OH-DPAT-induced effects in the rat: 1) reduction in brain 5-HT biosynthesis, measured as a decreased 5-hydroxytryptophan-accumulation after decarboxylase inhibition; 2) induction of the 5-HT1A behavior (flat body posture, forepaw treading and hindlimb abduction) in reserpine-pretreated animals; 3) reduction of body temperature; 4) inhibition of the cage-leaving response; and 5) reduction of 5-hydroxytryptophan- and quipazine-induced wet dog shakes. In addition, (S)-UH-301 reverses the 5-HT-induced inhibition of the forskolin stimulated cyclic AMP production in rat hippocampus without producing any effects per se in this assay. It is shown that high doses of (S)-UH-301 decrease rat brain biosynthesis of dopamine. These and previous data indicate that (S)-UH-301 also is a weakly potent dopamine-receptor agonist, but with a lower affinity for D2 as compared to 5-HT1A receptors. Thus, the data suggest that (S)-UH-301 is a 5-HT1A-receptor antagonist without intrinsic activity. Therefore, it is likely that (S)-UH-301 will become a valuable pharmacological tool in future 5-HT research.
authors.affiliation: Department of Medical Pharmacology, Uppsala Biomedical Centre, Uppsala University, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Björk
authors.forename: L J
authors.initials: LJ
authors.lastname: Cornfield
authors.forename: D L
authors.initials: DL
authors.lastname: Nelson
authors.forename: S E
authors.initials: SE
authors.lastname: Hillver
authors.forename: N E
authors.initials: NE
authors.lastname: Andén
authors.forename: T
authors.initials: T
authors.lastname: Lewander
authors.forename: U
authors.initials: U
authors.lastname: Hacksell
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000031:analogs & derivatives; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004295:Dihydroxyphenylalanine / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects; D012701:Serotonin / Q000096:biosynthesis*; D013764:Tetrahydronaphthalenes / Q000037:antagonists & inhibitors* / Q000494:pharmacology*
chemical_list: D011985:Receptors, Serotonin; D013764:Tetrahydronaphthalenes; C064282:UH 301; D012701:Serotonin; D004295:Dihydroxyphenylalanine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin