Pharmacological demarcation of the growth hormone, gut motility and feeding effects of ghrelin using a novel ghrelin receptor agonist

Endocrinology
Graeme FraserGloria Shaffer Tannenbaum

Abstract

The peptide hormone ghrelin exerts a wide spectrum of activities including the stimulation of GH release, feeding, and gastrointestinal motility, purportedly via the activation of a common receptor, GH secretagogue receptor (since renamed the GRLN-R) The aim of the present study was to determine whether these effects can be separated pharmacologically. Tranzyme Pharma (TZP)-101 is a small-molecule agonist with potent binding affinity (inhibitory constant = 16 nm) and full agonist activity (EC50 = 29 nm, maximum response = 111%) at the human recombinant GRLN-R. Pharmacokinetic profiling of TZP-101 in rat determined a plasma elimination half-life of 99 min and low blood-brain barrier permeability (0.09%). The pharmacological response to TZP-101, administered centrally [intracerebroventricular (icv)] or peripherally (iv), was evaluated in comparison with that of acylated ghrelin. Thus, TZP-101 (iv) accelerated gastric emptying of a liquid meal (2% methylcellulose) similarly to ghrelin (iv). IAlso, TZP-101 (icv) stimulated spontaneous, cumulative food intake in a similar manner to ghrelin (icv). However, unlike ghrelin, TZP-101 did not elicit significant GH release on either central or peripheral administration. Moreover, TZP-101 d...Continue Reading

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