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The GHSR\u20101a has a complex pharmacology, highlighted by G\u2010protein\u2013dependent and\u2014independent downstream signaling pathways and high basal constitutive activity. The functional selectivity and signaling bias of many GHSR\u20101a\u2013specific ligands has not been fully characterized. In this study, we investigated the pharmacologic properties of ghrelin, MK\u20100677, L692,585, and [\n                    <jats:sc>d<\/jats:sc>\n                    \u2010Lys3]\u2010growth hormone\u2013releasing peptide\u20106 (Dlys), JMV2959, and [\n                    <jats:sc>d<\/jats:sc>\n                    \u2010Arg(1),\n                    <jats:sc>d<\/jats:sc>\n                    \u2010Phe(5),\n                    <jats:sc>d<\/jats:sc>\n                    \u2010Trp(7, 9), Leu(11)]\u2010substance P (SP\u2010analog). We investigated their effect on basal GHSR\u20101a constitutive signaling, ligand\u2010directed downstream GHSR\u20101a signaling, functional selectivity, and signaling bias. Dlys behaved as a partial antagonist with a strong bias toward GHSR\u20101a\u2013\u03b2\u2010arrestin signaling, whereas JMV2959 acted as a full unbiased GHSR\u20101a antagonist. Moreover, the SP\u2010analog behaved as an inverse agonist increasing G\u2010protein\u2013dependent signaling, but only at high concentrations, whereas, at low concentrations, the SP\u2010analog attenuated \u03b2\u2010arrestin\u2013dependent signaling. Considering the limited success in the clinical development of GHSR\u20101a\u2013targeted drugs so far, these findings provide a novel insight into the pharmacologic characteristics of GHSR\u20101a ligands and their signaling bias, which has important implications in the design of novel, more selective GHSR\u20101a ligands with predictable functional outcome and selectivity for preclinical and clinical drug development.\u2014Ramirez, V. T., van Oeffelen, W. E. P. A., Torres\u2010Fuentes, C., Chru\u015bcicka, 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. FASEB J. 33, 518\u2013531 (2019).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201800655r","type":"journal-article","created":{"date-parts":[[2018,7,18]],"date-time":"2018-07-18T16:43:31Z","timestamp":1531932211000},"page":"518-531","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Differential functional selectivity and downstream signaling bias of ghrelin receptor antagonists and inverse agonists"],"prefix":"10.1096","volume":"33","author":[{"given":"Valerie T.","family":"Ramirez","sequence":"first","affiliation":[{"name":"Alimentary Pharmabiotic Centre (APC) Microbiome Ireland University College Cork  Cork Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wesley E. P. A.","family":"Van Oeffelen","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neuroscience University College Cork  Cork Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Torres-Fuentes","sequence":"additional","affiliation":[{"name":"Alimentary Pharmabiotic Centre (APC) Microbiome Ireland University College Cork  Cork Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Chru\u015bcicka","sequence":"additional","affiliation":[{"name":"Alimentary Pharmabiotic Centre (APC) Microbiome Ireland University College Cork  Cork Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clementine","family":"Druelle","sequence":"additional","affiliation":[{"name":"Alimentary Pharmabiotic Centre (APC) Microbiome Ireland University College Cork  Cork Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna 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