The kinetics of drug-receptor interactions can influence pharmacology. In vitro, the potencies of slowly associating agonists may be underestimated in assays capturing transient signaling events. In vivo, drugs with slow dissociation rates may display prolonged effects inconsistent with their pharmacokinetic profiles. This study evaluated 5-HT2B receptor agonists in radioligand binding assays and in transient, calcium flux assays and inositol phosphate accumulation assays. In binding assays, ergot derivatives demonstrated slow receptor association and dissociation rates, resulting in significantly reduced potency in calcium assays relative to inositol phosphate accumulation assays. A number of ergots produced wash-resistant 5-HT2B signaling that persisted for many hours but was not explained by slow receptor-dissociation kinetics. Mechanistic studies indicated that persistent signaling originated from internalized or sequestered receptors.
See article at J Pharmacol Exp Ther 2013, 347:645–659.
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