Synthesis and pharmacology of the enantiomers of UH301: Opposing interactions with 5‐HT1A receptors

Abstract

The (9-enantiomer of 5-fluoro-&hydroxy-2-(dipropylamino) tetralin [ (S)-2a; (S)-UH301] was the first reported 5-HTlA receptor antagonist. We now give a full account on the synthetic effort leading to the preparation of the racemate and the enantiomers of 2a. The crystal and molecular structure of 2a . HBr has been determined by X-ray diffraction and the absolute configuration has been deduced using statistical tests of the crystal!ographic R values. The unit cell is tetragonal (P4,2,2) with a = b = 13.2235(2), c = 39.560(1) A and contains two crystallographically independent molecules in each asymmetric unit. The two solid state conformers differ in the conformation of the N-propyl groups. The pharmacological characterization of the enantiomers was done by use of in vivo biochemical and behavioural assays in rats. The (R)-enantiomer of 2a is a 5-HTiA receptor agonist of low potency while (3-2a does not exhibit any agonist properties at 5-HTlA receptors. As a consequence of the opposing effects of the enantiomers, the racemate, rac-2a, does not produce any clear-cut effects in rats. The reduced efficacy of (S)-2a as compared to the well known 5HT1A receptor agonist t?-hydroxy-Z-(dipropy1amino)tetralin (1; 8-OH-DPAT) may be due to the fluoro-substituent induced negative potential of the aromatic ring.

Derivatives of (R)- and (S)-5-Fluoro-8-hydroxy-2-(dipropylamino)tetralin: Synthesis and Interactions with 5-HT1AReceptors

“…In fact, the replacement of one N -propyl group with a N -4-(8-aza-7,9-dioxospiro[4.5]decan-8-yl)butyl group increases the affinity throughout this series of compounds. With few exceptions, previous studies of 2-aminotetralin-based 5-HT 1A receptor ligands have demonstrated that the R -enantiomers have higher affinity than the antipodes. 7a,, In the present series, however, compounds 7 and 8 exhibited reversed enantiomeric affinity ratios, the S -enantiomers being more potent.…”

“… a The K i values are means ± standard errors, n = 2−3. b From ref a. c n = 1, slightly modified method.…”

“…However, no selective 5-HT 1A receptor antagonists have been registered. In fact, despite the numerous reports on 5-HT 1A receptor agonists and partial agonists during the past 15 years, it was only fairly recently that the first selective 5-HT 1A receptor antagonists were reported, ( S )-UH301 [( S )- 1 ], ( S )-WAY 100135 ( 2 ), and WAY 100635 ( 3 ) …”

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

“…The amine was converted into the hydrochloride salt, which was recrystallized to afford 1.72 g of pure 5‚HCl: mp 277-280 °C (lit. 50 (R)-2-(Benzylamino)-5-fluoro-8-hydroxytetralin Hydrobromide (6‚HBr). A stirred mixture of 5‚HCl (3.37 g, 10.5 mmol) and aqueous 48% HBr (100 mL) was refluxed (120 °C) under N2 for 7 h. The volatiles were evaporated under reduced pressure to give a solid residue which was recrystallized to afford 3.68 g of pure 6‚HBr: 1 (…”

“…mp 281-282 °C); [R] 22 D +60.8°(c 1.0, MeOH) [lit 50. [R]22 D +62.0°(c 1.0, MeOH)]; 1 H NMR (CD3OD) δ 1.74-1.90 (m, 1 H), 2.39-2.47 (m, 1 H), 2.60-2.80 (m, 2 H), 3.03-3.10 (m, 1 H), 3.36-3.44 (m, 1 H), 3.50-3.62 (m, 1 H), 3.82 (s, 3 H), 4.36 (s, 2 H), 6.77-6.81 (m, 1 H), 6.88-6.94 (m, 1 H), 7.45-7.58 (m, 5 H); 13 C NMR (CD3OD) δ 22.1 (d, 3 JC,F ) 3.7 Hz), 25.8, 27.7, 49.8, 55.6, 56.2, 109.3 (d, 3 JC,F ) 8.5 Hz), 113.6 (d, 2 JC,F ) 23.2 Hz), 123.8 (d, 3 JC,F ) 4.9 Hz), 124.6 (d, 2 JC,F ) 19.5 Hz), 130.4 (2C:s), 130.7, 131.0 (2C:s), 132.9, 154.6, 156.2 (d, 1 JC,F ) 235.6 Hz).…”