Constitutive activity of G protein coupled receptors and drug action

Abstract

Publisher Summary A new concept in G protein coupled receptor (GPCR)-mediated drug action is the occurrence of constitutive activity of GPCRs in the absence of agonist stimulation. Originally reported for the δ-opioid receptor in NG108-15 cells, this GPCR activity has now been described for a variety of GPCRs. Concomitant with the notion of agonist-independent signaling it has been realized that the constitutive GPCR activity can be inhibited by some antagonists (inverse agonists), but not by all antagonists (neutral antagonists) introducing the need for a pharmacological reclassification of GPCR antagonists. Moreover, for agonists and inverse agonist, a full spectrum of (negative) intrinsic activity from -1–0 can be observed. Neutral antagonists—that is, compounds with actually no intrinsic activity—are quite rare. Nevertheless, for some GPCRs, ligands with virtually no (negative) intrinsic activity are found. For example, the H 2 receptor has been identified as a ligand with very low intrinsic activity. Burimamide is able to block the effects of both an agonist (histamine) and an inverse agonist (cimetidine) on the cAMP levels in CHO cells expressing the H 2 receptor, with apparent pK B values that match its PK A value.