Synthesis and pharmacological characterization of a new benzoxazole derivative as a potent 5-HT3 receptor agonist Original Research Article

N-(2-Benzoxazol-2-yl-ethyl)-guanidine hydrochloride (10) was synthesized and pharmacologically tested. This compound showed high affinity for the 5-HT3 receptor (Ki=0.77 nM) and potently triggered the von Bezold–Jarisch reflex (BJR) in rats with an ED50=0.52 μg/kg iv and intrinsic activity next to 1 (i.a.=0.94). This stimulant effect was abolished by pretreatment with the 5-HT3 receptor antagonist granisetron and was subject to a rapid and pronounced tachyphylaxis, due to desensitization of the peripheric cardiac 5-HT3 receptor. Consequently, 10 acts as an in vivo 5-HT3 antagonist inhibiting the BJR responses evoked by submaximal doses of 5-HT with an ID50=5.8 μg/kg iv.