Synthesis and pharmacological characterization of a new benzoxazole derivative as a potent 5-HT3 receptor agonist.
N-(2-Benzoxazol-2-yl-ethyl)-guanidine hydrochloride (10) was synthesized and pharmacologically tested. This compound showed high affinity for the 5-HT(3) receptor (K(i)=0.77 nM) and potently triggered the von Bezold-Jarisch reflex (BJR) in rats with an ED(50)=0.52 microg/kg iv and intrinsic activity next to 1 (i.a.=0.94). This stimulant effect was abolished by pretreatment with the 5-HT(3) receptor antagonist granisetron and was subject to a rapid and pronounced tachyphylaxis, due to desensitization of the peripheric cardiac 5-HT(3) receptor. Consequently, 10 acts as an in vivo 5-HT(3) antagonist inhibiting the BJR responses evoked by submaximal doses of 5-HT with an ID(50)=5.8 microg/kg iv.
López-Tudanca
Pedro Luis
PL
Department of Research, FAES FARMA, S.A., Máximo Aguirre 14, 48940 Leioa, Vizcaya, Spain.
Labeaga
Luis
L
Innerárity
Ana
A
Alonso-Cires
Luisa
L
Tapia
Inés
I
Mosquera
Ramón
R
Orjales
Aurelio
A
D000818:Animals; D001583:Benzoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D017829:Granisetron / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D012018:Reflex / Q000187:drug effects; D058827:Serotonin 5-HT3 Receptor Agonists; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013618:Tachyphylaxis
D001583:Benzoxazoles; D017829:Granisetron; D058827:Serotonin 5-HT3 Receptor Agonists; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists