Derivatives of (R)- and (S)-5-Fluoro-8-hydroxy-2-(dipropylamino)tetralin:  Synthesis and Interactions with 5-HT_1AReceptors

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.

4-(Dimethylamino)pyridine (DMAP) as an Acid-Modulated Donor Ligand for PAH Dearomatization

“…Tetralin cores, as seen highlighted in Figure , are present in many naturally occurring substances as well as pharmaceuticals. − They are typically synthesized from the cyclization of arenes or from hydrogenation of a naphthalene precursor. Our interest in using η 2 -coordinated aromatic molecules as scaffolds for the preparation of novel alicyclic molecules , led us to investigate ways to prepare functionalized tetralins from the metal-promoted, tandem additions to η 2 -naphthalene complexes, as well as their anthracene-derived analogues. − …”

Novel (R)-2-Amino-5-fluorotetralins: Dopaminergic Antagonists and Inverse Agonists

“…Among the secondary amines, the N-alkyl substituent considerably influenced the receptor binding affinities (Table 2); the introduction of a Nbenzyl group (8) in the primary amine 9 decreased the affinity for the DA D 3 receptors but had little effect on the DA D 2 and the 5-HT 1A receptor affinity. The N-isopropyl derivative 13 displayed low affinity at the DA D 2 and D 3 receptors, whereas the 5-HT 1A receptors appear to better accommodate an N-isopropyl group.…”

“…( R )-2-[ [ 4-(8-Aza-7,9-dioxospiro [ 4.5 ] decan-8-yl)butyl]amino ] -5-fluorotetralin Hydrochloride (17·HCl). A mixture of 9 (116 mg, 0.70 mmol), 8-(4-bromobutyl)-8-azaspiro[4.5]decane-7,9-dione , (233 mg, 0.77 mmol), K 2 CO 3 (388 mg, 2.81 mmol), and KI (1.2 mg, 7 μmol) in DMF (1.5 mL) was stirred under N 2 for 23 h at room temperature. The mixture was diluted with ether, filtered, and concentrated.…”

“…The starting material (R)-2-amino-5-fluoro-8-methoxytetralin (4) 8 contained trace amounts of 2-amino-8-methoxytetralin, and it was therefore converted into the corresponding N-benzyl derivative 5 14 to facilitate purification. Pure 5 was prepared by reductive alkylation 22 of 4 using benzaldehyde and NaCNBH 3 followed by repetitive column chromatography.…”

“…In an ongoing project, we study how the efficacy of 2-aminotetralin derivatives at dopamine (DA) D 2 and D 3 receptors can be modified by relatively small structural changes. Although several 2-aminotetralin-derived DA receptor ligands, such as ( S )-5-hydroxy-2-(dipropylamino)tetralin (5-OH-DPAT), are highly efficacious, various analogues, such as ( R )-5-F-DPAT ( 1 ), ( R )-5-OH-DPAT, (1 S ,2 R )-UH-232 ( 2 ), and (1 S ,2 R )-AJ-76 ( 3 ), have been characterized as DA D 2 receptor partial agonists, antagonists, or inverse agonists. ,, This indicates that the 2-aminotetralin moiety is particularly well suited for studies of the relationship between structure and intrinsic activity.

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