Potent, selective tetrahydro-beta-carboline antagonists of the serotonin 2B (5HT2B) contractile receptor in the rat stomach fundus.
A series of potent, selective 5HT2B receptor antagonists has been identified based upon yohimbine, with SAR studies resulting in a 1000-fold increase in 5HT2B receptor affinity relative to the starting structure (-log KBS > 10.0 have been obtained). These high-affinity tetrahydro-beta-carboline antagonists are able to discriminate among the 5HT2 family of serotonin receptors, with members of the series showing selectivities of more than 100-fold versus both the 5HT2A and 5HT2C receptors based upon radioligand binding and functional assays. As the first compounds reported with such selectivity and enhanced receptor affinity, these tetrahydro-beta-carboline antagonists are useful tools for elucidating the role of serotonin acting at the 5HT2B receptor in normal and disease physiology.
Audia
J E
JE
Lilly Research Laboratories, Division of Eli Lilly & Company, Indianapolis, Indiana 46285, USA.
Evrard
D A
DA
Murdoch
G R
GR
Droste
J J
JJ
Nissen
J S
JS
Schenck
K W
KW
Fludzinski
P
P
Lucaites
V L
VL
Nelson
D L
DL
Cohen
M L
ML
D000818:Animals; D002243:Carbolines / Q000138:chemical synthesis / Q000494:pharmacology*; D002460:Cell Line; D006224:Cricetinae; D005748:Gastric Fundus; D066298:In Vitro Techniques; D008297:Male; D008647:Mesocricetus; D051379:Mice; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D015016:Yohimbine / Q000737:chemistry
D002243:Carbolines; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D015016:Yohimbine; C009804:tryptoline