N,N-Dialkylated monophenolic trans-2-phenylcyclopropylamines: novel central 5-hydroxytryptamine receptor agonists.
N,N-Dialkylated monophenolic derivatives of trans-2-phenylcyclopropylamine were synthesized and tested for central 5-hydroxytryptamine (5-HT) and dopamine (DA) receptor stimulating activity by use of a biochemical test method in rats. A hydroxy substituent in the 2- or 3-position of the phenyl ring was required for 5-HT-receptor stimulation. N,N-Diethyl or N,N-di-n-propyl substitution gave the most potent 5-HT-receptor agonists. The 4-hydroxy and 3,4-dihydroxy derivatives of trans-2-phenyl-N,N-di-n-propylcyclopropylamine were inactive at central DA and 5-HT receptors. In contrast, the corresponding 3-hydroxy derivative 18 and some of its derivatives weakly affected both DA and NE synthesis. Two of the most potent 5-HT-receptor agonists, trans-2-(2-hydroxyphenyl)-N,N-di-n-propylcyclopropylamine (8) and the 3-hydroxy isomer 18 were resolved into the enantiomers. The 1R,2S enantiomers of 8 and 18 displayed 5-HT activity, while the 1S,2R enantiomers were inactive. Compound (1R,2S)-18, but not (1R,2S)-8, weakly affected rat brain DA and NE synthesis.
Arvidsson
L E
LE
Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Center, University of Uppsala, Sweden.
Johansson
A M
AM
Hacksell
U
U
Nilsson
J L
JL
Svensson
K
K
Hjorth
S
S
Magnusson
T
T
Carlsson
A
A
Lindberg
P
P
Andersson
B
B
D000478:Alkylation; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008968:Molecular Conformation; D010636:Phenols / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014191:Tranylcypromine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
D010636:Phenols; D011985:Receptors, Serotonin; D014191:Tranylcypromine