Potent achiral agonists of the ghrelin (growth hormone secretagogue) receptor. Part I: Lead identification

Heightman, Tom D.; Scott, J. F.; Longley, Mark; Bordas, Vincent; Dean, David K.; Elliott, Richard L.; Hutley, Gail; Witherington, Jason; Abberley, Lee; Passingham, B. J.; Berlanga, Manuela; Frailes, Maite de los; Wise, Alan; Powney, Ben; Muir, Alison I.; McKay, Fiona C.; Butler, Sharon; Winborn, Kim; Gardner, C.; Darton, Jill; Campbell, C. A.; Sanger, Gareth J.

doi:10.1016/j.bmcl.2007.09.067

Cited by 17 publications

(8 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Synthetic GhrR agonists have been shown previously to stimulate GI motility effectively when injected intravenously (Greenwood-Van Meerveld et al, 2004;Heightman et al, 2007;Venkova et al, 2007). Here, we have demonstrated potent efficacy of GhrR agonists on stimulated gastric emptying, small intestinal transit, and fecal output in addition to stimulating food intake.…”

Section: Discussionmentioning

confidence: 50%

Enhanced Gastrointestinal Motility with Orally Active Ghrelin Receptor Agonists

Charoenthongtrakul¹,

Giuliana²,

Longo³

et al. 2009

J Pharmacol Exp Ther

View full text Add to dashboard Cite

The orexigenic peptide ghrelin has been shown to have prokinetic activity in the gastrointestinal (GI) system of several species, including humans. In this series of experiments, we have evaluated the prokinetic activity of novel, small-molecule ghrelin receptor (GhrR) agonists after parenteral and peroral dosing in mice and rats. Gastric emptying, small intestinal transport, and fecal output were determined after intraperitoneal and intracerebroventricular dosing of GhrR agonists, using ghrelin as a positive control. These same parameters were evaluated after oral gavage dosing of the synthetic agonists. Regardless of dose route, GhrR agonist treatment increased gastric emptying, small intestinal transit, and fecal output. However, fecal output was only increased by GhrR agonist treatment if mice were able to feed during the stimulatory period. Thus, GhrR agonists can stimulate upper GI motility, and the orexigenic action of the compounds can indirectly contribute to prokinetic activity along the entire GI tract. The orexigenic and prokinetic effects of either ghrelin or small-molecule GhrR agonists were selective for the GhrR because they were absent when evaluated in GhrR knockout mice. We next evaluated the efficacy of the synthetic GhrR agonists dosed in a model of opiate-induced bowel dysfunction induced by a single injection of morphine. Oral dosing of a GhrR agonist normalized GI motility in opiate-induced dysmotility. These data demonstrate the potential utility of GhrR agonists for treating gastrointestinal hypomotility disorders.

show abstract

Section: Discussionmentioning

confidence: 50%

Enhanced Gastrointestinal Motility with Orally Active Ghrelin Receptor Agonists

Charoenthongtrakul¹,

Giuliana²,

Longo³

et al. 2009

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…There was no treatment effect on swim speed on either of the test days. Data expressed as means±SEM (n=10) Patchett et al 1995;Heightman et al 2007;Witherington et al 2008), the aim of these studies was to determine if structurally diverse small-molecule ghrelin receptor agonists are also pro-cognitive.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, a series of potent, achiral ghrelin receptor agonists exemplified by SB-791016-A were identified via high-throughput screening and data-mining approaches (Heightman et al 2007). The "drug-like" properties of these molecules were subsequently enhanced in a series of lead optimisation steps, which ultimately led to the identification of GSK894490A, an orally bioavailable and selective nonpeptide GHS-R agonist (Witherington et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Cognitive enhancing effects of ghrelin receptor agonists

et al. 2009

Self Cite

View full text Add to dashboard Cite

These results demonstrate that the small-molecule ghrelin receptor agonists profiled here readily cross the blood/brain barrier and elicit pro-cognitive effects in recognition and spatial learning and memory tests. Based on these observations, the central ghrelin receptor would appear to be a chemically tractable receptor and perhaps should be considered as a new drug target for therapeutic approaches to treat diseases affecting cognition.

show abstract

“…More recently, 25 has been further optimized through successful replacement of the benzyloxy-group with a gem-difluoropropyl benzene, giving 26, which has an increased in vitro potency (EC 50 : 0.27 nM), better efficacy, and improved exposure and oral bioavailability in rat (F 26%) when compared to 25 [69]. A high-throughput screening (HTS) approach was used to identify agonists of the ghrelin receptor which were devoid of the peptide-like nature of privileged fragments seen thus far [70]. The indoline hit 27, originally a 5-HT 1B receptor antagonist (5-HT 1B pK i : 7.9), was optimized to give SB-791016, 28, a potent ghrelin agonist with good intrinsic activity (i.a.…”

Section: Ghrelin Receptor Agonistsmentioning

confidence: 99%