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Synthesis and pharmacology of the enantiomers of UH301: Opposing interactions with 5‐HT 1A receptors
Author(s) -
Hillver SvenErik,
Björk Lena,
Höök Berit Backlund,
Cortizo Lourdes,
Nordvall Gunnar,
Johansson Anette M.,
Ertan Anne,
Csöregh Ingeborg,
Johansson Lars,
Lewander Tommy,
Hacksell Uli
Publication year - 1996
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/(sici)1520-636x(1996)8:8<531::aid-chir1>3.0.co;2-c
Subject(s) - chemistry , enantiomer , stereochemistry , agonist , tetralin , substituent , absolute configuration , conformational isomerism , chiral column chromatography , partial agonist , chirality (physics) , receptor , molecule , biochemistry , organic chemistry , catalysis , nambu–jona lasinio model , chiral symmetry breaking , physics , quantum mechanics , quark
The ( S )‐enantiomer of 5‐fluoro‐8‐hydroxy‐2‐(dipropylamino) tetralin [( S )‐ 2a; ( S )‐UH301] was the first reported 5‐HT 1A 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 ( P4 1 2 1 2 ) 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‐HT 1A receptor agonist of low potency while ( S )‐ 2a does not exhibit any agonist properties at 5‐HT 1A 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‐HT 1A 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.