6,7,8,9-Tetrahydro-N,N-di-n-propyl-3H-benzindol-8-amines. Derivatives as potent and orally active serotonin 5-HT1A receptor agonists.
Derivatives and isosteric derivatives of the potent 5-HT1A agonist 8-(di-n-propylamino)-6,7,8,9- tetrahydro-3H-benz[e]indole-1-carbaldehyde (5) were prepared and evaluated in vivo and in vitro for serotonergic and dopaminergic activity. The 1-cyano analog 8 was found to be almost equipotent to 5 and the previously described 2-cyano derivative 6, while a 1-chloro and 1-(1,1,1-trifluoroethyl) substituent (9 and 10, respectively) formed less potent derivatives. The isosteric 6,7,8,9-tetrahydro-1H-benz[g]indoles 4 and 12-15 showed surprisingly low affinity or activity at both serotonergic and dopaminergic systems. The interpretations of these results by means of drug-receptor interactions at the 5-HT1A subtype are discussed. Compounds 6 and 8 were found to have high oral bioavailability in the rat (63% and 54%, respectively).
Stjernlöf
P
P
Department of Pharmacology, Göteborg University, Sweden.
Elebring
T
T
Nilsson
J
J
Andersson
B
B
Lagerkvist
S
S
Svensson
K
K
Ekman
A
A
Carlsson
A
A
Wikström
H
H
D000818:Animals; D001667:Binding, Competitive; D001682:Biological Availability; D004563:Electrochemistry; D007211:Indoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
D007211:Indoles; D017366:Serotonin Receptor Agonists; C082404:8-(di-n-propylamino)-6,7,8,9-tetrahydro-3H-benz(e)indole-1-carbaldehyde