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 1H NMR spectroscopic analysis of the corresponding diastereomeric (-)-(R)-1,1'-binaphthyl-2,2'-diylphosphoric acid salts utilizing 13C 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."
Höök
B B
BB
Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Center, Uppsala University, Sweden.
Johansson
A M
AM
Hjorth
S
S
Sundell
S
S
Hacksell
U
U
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism*; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D003460:Crystallization; D003956:Dialysis; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008968:Molecular Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism*; D013237:Stereoisomerism; D014961:X-Ray Diffraction
D017448:Receptors, Dopamine D2; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C046716:5-hydroxy-2-methyl-2-(di-n-propylamino)tetralin