title: Derivatives of (R)- and (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin: synthesis and interactions with 5-HT1A receptors.
abstract: Analogs of the 5-HT1A receptor antagonist (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin [(S)-1,(S)-UH301] have been prepared. The C8-substituent has been varied, and in some derivatives one of the N-propyl groups has been exchanged for a 4-(8-aza-7,9-dioxospiro[4.5]decan-8-yl)-butyl group. The novel compounds have been evaluated for affinity to rat brain 5-HT1A receptors in competition experiments with [3H]-8-OH-DPAT. In addition, the efficacy of the compounds was assessed by their ability to inhibit the VIP-stimulated cAMP formation in GH4ZD10 cells expressing rat 5-HT1A receptors. Varying degrees of intrinsic activity was revealed among the compounds tested, i.e., the profiles ranged from full agonists to antagonists. All R-enantiomers are characterized as full agonists at 5-HT1A receptors, whereas partial agonists or antagonists were found among the corresponding S-enantiomers. Substitution of one of the N-propyl groups for a 4-(8-aza-7,9-dioxospiro[4.5]decan-8-yl)butyl group seems to increase efficacy as well as affinity for 5-HT1A receptors. A favorable interaction with an accessory binding site by the N-4-(8-aza-7,9-dioxospiro[4.5]decan-8-yl)butyl group may contribute to the increased affinity.
authors.affiliation: Uppsala University, Uppsala Biomedical Centre, Sweden.
authors.forename: B B
authors.initials: BB
authors.lastname: Höök
authors.forename: L
authors.initials: L
authors.lastname: Cortizo
authors.forename: A M
authors.initials: AM
authors.lastname: Johansson
authors.forename: A
authors.initials: A
authors.lastname: Westlind-Danielsson
authors.forename: N
authors.initials: N
authors.lastname: Mohell
authors.forename: U
authors.initials: U
authors.lastname: Hacksell
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D015394:Molecular Structure; D051381:Rats; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
chemical_list: D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C064282:UH 301; D014660:Vasoactive Intestinal Peptide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000242:Cyclic AMP