A novel class of 5-HT2A receptor antagonists: aryl aminoguanidines.
Local delivery of serotonin (5-HT) produces a rapid edematous response in soft tissues via increased fluid extravasation which is prevented by 5-HT2 antagonists such as ketanserin or mianserin. Here we report the effects of a new class of aminoguanidine 5-HT2 antagonists, with relative selectivity for 5-HT2A receptors which are potent inhibitors of 5-HT-induced paw edema in the rat. Radioligand binding studies with 125I DOI on human 5-HT2A and 5-HT2C receptors and with 3H-5-HT on human 5-HT2B receptors demonstrated that, LY314228, and LY320954 displayed some selectivity for the 5-HT2A receptor. When compared to binding at other 5-HT2 receptor subtypes, LY314228 had an 18.6-fold greater affinity for the 5-HT2A site over the 5-HT2B site, and 2.6 fold greater at the 5-HT2C site. LY320954 displayed similar preference for 5-HT2A sites. Both compounds also inhibited 5-HT-induced paw swelling in rats, with ED50's of 6.4 and 4.8 mg/kg (for LY314228 and LY320954, respectively). These studies offer evidence for a novel class of pharmacophores for the 5-HT2 receptor family which show greater relative affinities for the 5-HT2A receptor subclass.
Bryant
H U
HU
Division of Endocrine Research, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Nelson
D L
DL
Button
D
D
Cole
H W
HW
Baez
M B
MB
Lucaites
V L
VL
Wainscott
D B
DB
Whitesitt
C
C
Reel
J
J
Simon
R
R
Koppel
G A
GA
D000818:Animals; D002461:Cell Line, Transformed; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D004487:Edema / Q000139:chemically induced; D005260:Female; D006146:Guanidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008647:Mesocricetus; D015394:Molecular Structure; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*
D006146:Guanidines; C101786:LY 314228; C101787:LY 320954; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D012701:Serotonin