5-HT1D receptor agonist properties of novel 2-[5-[[(trifluoromethyl)sulfonyl]oxy]indolyl]ethylamines and their use as synthetic intermediates.
2-[5-[[(trifluoromethyl)sulfonyl]oxy]-1H-indol-3-yl]ethylamine (18), its N,N-di-n-propyl (12), N,N-diethyl (13), and N,N-dimethyl (14) derivatives, and 4-[3-[2-(N,N-dimethylamino)ethyl]-1H-indol-3-yl]-N-(p-methoxybenzyl) acrylamide (GR46611, 19) were synthesized and tested for binding affinities to cloned 5-HT1A, 5-HT1D alpha, 5-HT1D beta, and D2 receptors. In addition, the intrinsic efficacy was measured as the reduction of forskolin-stimulated cAMP in cells transfected with 5-HT1D alpha and 5-HT1D beta receptors in vitro. The 5-substituted indolyethylamines investigated displayed agonist activity at the 5-HT1D receptors with varying degrees of preference for the 5-HT1D alpha vs the 5-HT1D beta receptors. The primary amine and N,N-dimethyl substitution seemed to be optimal for 5-HT1D alpha affinity. Furthermore, the N,N-diethyl (13) and N,N-dimethyl (14) derivatives showed a 10-25 times preference for the 5-HT1D alpha vs the 5-HT1D beta receptor. In addition, all of the novel compounds showed affinity for the 5-HT1A receptor in vitro (Ki values ranging from 18 to 40 nM). The most promising derivative 14 was virtually devoid of central 5-HT1A agonist activity in rats, as determined by in vivo biochemical assays. Paradoxically, 14, like 19, induced a hypothermic response and a decrease in 5-HIAA levels in the prefrontal cortex and hypothalamus in guinea pigs after systemic administration. Sumatriptan failed to produce either of these effects due to a poor brain penetration.
Barf
T A
TA
Department of Medicinal Chemistry, University of Groningen, The Netherlands.
de Boer
P
P
Wikström
H
H
Peroutka
S J
SJ
Swensson
K
K
Ennis
M D
MD
Ghazal
N B
NB
McGuire
J C
JC
Smith
M W
MW
D006916:5-Hydroxytryptophan / Q000378:metabolism; D000178:Acrylamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000032:analysis / Q000378:metabolism; D005021:Ethylamines / Q000138:chemical synthesis / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007035:Hypothermia; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000178:Acrylamides; D005021:Ethylamines; D011985:Receptors, Serotonin; D011994:Recombinant Proteins; D012702:Serotonin Antagonists; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D006916:5-Hydroxytryptophan; D000242:Cyclic AMP