Differential functional selectivity and downstream signaling bias of ghrelin receptor antagonists and inverse agonists.

The ghrelin receptor [growth hormone secretagogue receptor (GHSR)-1a] represents a promising pharmacologic target for the treatment of metabolic disorders， including obesity and cachexia， via central appetite modulation. The GHSR-1a has a complex pharmacology， highlighted by G-protein-dependent and -independent downstream signaling pathways and high basal constitutive activity. The functional selectivity and signaling bias of many GHSR-1a-specific ligands has not been fully characterized. In this study， we investigated the pharmacologic properties of ghrelin， MK-0677， L692，585， and [d-Lys3]-growth hormone-releasing peptide-6 (Dlys)， JMV2959， and [d-Arg(1)，d-Phe(5)，d-Trp(7， 9)，Leu(11)]-substance P (SP-analog). We investigated their effect on basal GHSR-1a constitutive signaling， ligand-directed downstream GHSR-1a signaling， functional selectivity， and signaling bias. Dlys behaved as a partial antagonist with a strong bias toward GHSR-1a-β-arrestin signaling， whereas JMV2959 acted as a full unbiased GHSR-1a antagonist. Moreover， the SP-analog behaved as an inverse agonist increasing G-protein-dependent signaling， but only at high concentrations， whereas， at low concentrations， the SP-analog attenuated β-arrestin-dependent signaling. Considering the limited success in the clinical development of GHSR-1a-targeted drugs so far， these findings provide a novel insight into the pharmacologic characteristics of GHSR-1a ligands and their signaling bias， which has important implications in the design of novel， more selective GHSR-1a ligands with predictable functional outcome and selectivity for preclinical and clinical drug development.-Ramirez， V. T.， van Oeffelen， W. E. P. A.， Torres-Fuentes， C.， Chruścicka， B.， Druelle， C.， Golubeva， A. V.， van de Wouw， M.， Dinan， T. G.， Cryan， J. F.， Schellekens， H. Differential functional selectivity and downstream signaling bias of ghrelin receptor antagonists and inverse agonists.