Synthesis of (+)‐(R)‐ and (−)‐(S)‐5‐hydroxy‐2‐methyl‐2‐dipropylaminotetralin: Effects on rat hippocampal output of 5‐HT, 5‐HIAA, and DOPAC as determined by in vivo microdialysis

Racemic 5‐methoxy‐2‐methyl‐2‐dipropylaminotetralin ( 3 ) has been prepared by a short synthetic route, in which the N , N ‐dipropyliminium perchlorate of 5‐methoxy‐2‐tetralone ( 4 ) is a key intermediate. Racemic 3 was resolved by crystallization of the corresponding diastereomeric di‐ p ‐toluoyltartrates. The enantiomeric excess (%ee) of the phenolic derivatives of (+)‐(R)‐ and (−)‐(S)‐3 [(+)‐(R)‐ and (−)‐(S)‐2] was determined by 1 HNMR spectroscopic analysis of the corresponding diastereomeric (−)‐(R)‐1,1′‐binaphthyl‐2,2′‐diylphosphoric acid salts utilizing 13 C satellites. X‐ray crystallography established the absolute configuration of (−)‐(S)‐2 · HCl. The enantiomers of 2 were tested for hippocampal output of 5‐hydroxytryptamine, 5‐hydroxyindoleacetic acid, and dihydroxyphenylacetic acid in rats by use of in vivo microdialysis. The (−)‐(S)‐enantiomer appeared to affect 5‐HT‐turnover, whereas (+)‐(R)‐ 2 was inactive. Results obtained provide support for the previously reported hypothesis that the inactivity of (−)‐(S)‐ 2 at central DA receptors is caused by the steric bulk of the C(2)‐methyl group. This makes it possible to define a “DA D2 receptor essential volume.” © 1993 Wiley‐Liss, Inc.