Synthesis and pharmacology of the enantiomers of UH301: Opposing interactions with 5-HT1A receptors |
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Authors: | Sven-Erik Hillver,Lena Bjö rk,Berit Backlund Hö ö k,Lourdes Cortizo,Gunnar Nordvall,Anette M. Johansson,Anne Ertan,Ingeborg Csö regh,Lars Johansson,Tommy Lewander,Uli Hacksell |
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Abstract: | The (S)-enantiomer of 5-fluoro-8-hydroxy-2-(dipropylamino) tetralin [(S)- 2a; (S)-UH301] was the first reported 5-HT1A 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 crystallographic R values. The unit cell is tetragonal (P41212) with a = b = 13.2235 (2), c = 39.560(1) Å 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-HT1A receptor agonist of low potency while (S)- 2a does not exhibit any agonist properties at 5-HT1A 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 5-HT1A receptor agonist 8-hydroxy-2-(dipropylamino)tetralin ( 1; 8-OH-DPAT) may be due to the fluoro-substituent induced negative potential of the aromatic ring. Chirality 8:531–544, 1996. © 1997 Wiley-Liss, Inc. |
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Keywords: | 5-HT1A receptor antagonists UH301 enantiomers rat biochemistry |
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