Growth hormone secretagogues and growth hormone releasing peptides act as orthosteric super-agonists but not allosteric regulators for activation of the G protein Gαo1 by the ghrelin receptor

Kirstie A. Bennett, Christopher J. Langmead, Alan Wise, Graeme Milligan

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30 Citations (Scopus)


Some growth hormone secretagogues act as agonists at the ghrelin receptor and have been described as "ago-allosteric" ligands because of an ability to also modulate the maximum efficacy and potency of ghrelin (Holst et al., 2005). In membranes prepared from cells coexpressing the human ghrelin receptor and the G protein Gαo1, N-[1(R)-1, 2-dihydro-1-ethanesulfonylspiro-3H-indole-3,4′-piperidin)-1′-yl] carbonyl-2-(phenylmethoxy)-ethyl-2-amino-2-methylpropanamide (MK-677), growth hormone-releasing peptide 6 (GHRP-6), and the 2(R)-hydroxypropyl derivative of 3-amino-3-methyl-N-(2,3,4,5-tetrahydro-2-oxo-1-([2′-(1H-tetrazol-5-yl) (1,1′-biphenyl)-4-yl]methyl)-1H-1-benzazepin-3(R-)-yl)-butanamide (L-692,585) each functioned as direct agonists, and each displayed higher efficacy than ghrelin. The effect of multiple, fixed concentrations of each of these ligands on the function and concentration-dependence of ghrelin and the effect of multiple, fixed concentrations of ghrelin on the action of MK-677, GHRP-6, and L-692,585 was analyzed globally according to a modified version of an operational model of allosterism that accounts for allosteric modulation of affinity, efficacy, and allosteric agonism. Each of the data sets was best fit by a model of simple competition between a partial and a full agonist. Both positive and negative allosteric modulators are anticipated to alter the kinetics of binding of an orthosteric agonist. However, none of the proposed ago-allosteric regulators tested had any effect on the dissociation kinetics of 125I-[His]-ghrelin, and GHRP-6 and MK-677 were able to fully displace 125I-[His]-ghrelin from the receptor. At least in the system tested, each of the ligands acted in a simple competitive fashion with ghrelin as demonstrated by analysis according to a model whereby ghrelin is a partial agonist with respect to each of the synthetic agonists tested.

Original languageEnglish
Pages (from-to)802-811
Number of pages10
JournalMolecular Pharmacology
Issue number4
Publication statusPublished - Oct 2009
Externally publishedYes

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