Ht3 Receptor Family

In contrast to all other known 5-HT receptors, the 5-HT3 receptor is a ligand-gated ion channel [68]. 5-HT3 antagonists are well known in the literature and several are currently on the market for the treatment of chemotherapy-induced emesis and/ or irritable bowel syndrome [69]. The chemistry and pharmacology of selective 5-HT3 agonists is less well understood, although the state of the art in that area has been reviewed recently [70]. Efforts continue to identify structural variations that are tolerated within the basic 5-HT3 antagonist pharmacophore. SAR studies on fused heterocyclic thiophene analogs resulted in the identification of 21, which displayed good potency for rat 5-HT3 receptors (Ki 3.92nM) and excellent selectivity over 5-HT4 [71]. In a series of benzoisoindolones [72], compound 22 displayed good 5-HT3 affinity (Ki 1.2 nM), in vitro antagonist activity (IC50 12 nM) and blocked the Bezold-Jarisch reflex (ID50 2.8 mg/kg i.v.). Compound 22 also prevented scopolamine-induced amnesia in a passive avoidance test at doses of 0.01-1.0 mg/kg i.p. New thienopyrimidines, represented by 23 [73], displayed moderate affinity for 5-HT3 receptors (Ki 33 nM) and > 100-fold selectivity for 5-HT4. Functional studies suggest that 23 may act as a noncompetitive antagonist.


YM-31636 (24) is the most potent 5-HT3 agonist in a series of indenothiazoles [14]. The compound displayed potent affinity for human 5-HT3 receptors (Ki 0.2 nM) and excellent selectivity for a number of biogenic amine receptors, although data for 5-HT4 were not presented. This compound demonstrated agonist activity in isolated guinea pig colon and anticonstipation effects in ferrets at doses of 0.03-3 mg/kg p.o.

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