SYNTHESIS AND PHARMACOLOGY OF THE ENANTIOMERS OF UH301 - OPPOSING INTERACTIONS WITH 5-HT1A RECEPTORS

The (S)-enantiomer of 5-fluoro-8-hydroxy-2-(dipropylamino) tetralin [( S)-2a; (S)-UH301] was the first reported 5-HT1A receptor antagonist. W e now give a full account on the synthetic effort leading to the prepa ration of the racemate and the enantiomers of 2a. The crystal and mole cular structure of 2a . HBr has been determined by X-ray diffraction a nd the absolute configuration has been deduced using statistical tests of the crystallographic R values. The unit cell is tetragonal (P4(1)2 (1)2) with a = b = 13.2235(2), c = 39.560(1) Angstrom and contains two crystallographically independent molecules in each asymmetric unit. T he two solid state conformers differ in the conformation of the N-prop yl groups. The pharmacological characterization of the enantiomers was done by use of in vivo biochemical and behavioural assays in rats. Th e (R)enantiomer of 2a is a 5HT(1A) receptor agonist of low potency whi le (S)-2a does not exhibit any agonist properties at 5-HT1A receptors. As a consequence of the opposing effects of the enantiomers, the race mate, rac-2a, does not produce any clear-cut effects in rats. The redu ced efficacy of (S)-2a as compared to the well known 5-HT1A receptor a gonist 8-hydroxy-2-(dipropylamino)tetralin (1;8-OH-DPAT) may be due to the fluoro-substituent induced negative potential of the aromatic rin g. (C) 1997 Wiley-Liss, Inc.