Ghrelin receptor modulators: a patent review (2011 – 2014)

Costantino, Luca; Barlocco, Daniela

doi:10.1517/13543776.2014.941531

Cited by 9 publications

(14 citation statements)

References 80 publications

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“…The substance JMV2959, a widely accepted standard experimental GHS-R1A antagonist, did not reach clinical research yet. So far, from a range of different substances with ghrelin antagonistic effects, only one GHS-R1A inverse agonist, substance PF-5190457, has complied with the strict requirements and has been recently approved for a clinical study in alcoholics [ 11 , 70 ]. However, the potential use of ghrelin antagonism for the treatment of methamphetamine addiction, which was confirmed in our study, can be considered as a useful novel mechanism/approach, which could also be applied to other appropriate clinically acceptable substances with GHS-R1A antagonistic effects.…”

Section: Discussionmentioning

confidence: 99%

Ghrelin Receptor Antagonism of Methamphetamine-Induced Conditioned Place Preference and Intravenous Self-Administration in Rats

Havlickova

Charalambous

Lapka

et al. 2018

IJMS

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Methamphetamine abuse imposes a significant burden on individuals and society worldwide, and an effective therapy of methamphetamine addiction would provide distinguished social benefits. Ghrelin significantly participates in reinforcing neurobiological mechanisms of stimulants, including amphetamines; thus, ghrelin antagonism is proposed as a promising addiction treatment. The aim of our study was to elucidate whether the pretreatment with growth hormone secretagogue receptor (GHS-R1A) antagonist, substance JMV2959, could reduce the methamphetamine intravenous self-administration (IVSA) and the tendency to relapse, and whether JMV2959 could reduce or prevent methamphetamine-induced conditioned place preference (CPP) in rats. Following an adequate maintenance period, JMV2959 3 mg/kg was administered intraperitoneally 20 min before three consequent daily 180 min sessions of methamphetamine IVSA under a fixed ratio FR1, which significantly reduced the number of active lever-pressings, the number of infusions, and the amount of the consumed methamphetamine dose. Pretreatment with JMV2959 also reduced or prevented relapse-like behavior tested in rats on the 12th day of the abstinence period. Pretreatment with JMV2959 significantly reduced the expression of methamphetamine-induced CPP. Simultaneous administration of JMV2959 with methamphetamine during the conditioning period significantly reduced the methamphetamine-CPP. Our results encourage further research of the ghrelin antagonism as a potential new pharmacological tool for methamphetamine addiction treatment.

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Section: Discussionmentioning

confidence: 99%

Ghrelin Receptor Antagonism of Methamphetamine-Induced Conditioned Place Preference and Intravenous Self-Administration in Rats

Havlickova

Charalambous

Lapka

et al. 2018

IJMS

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“…This prompted the research of ghrelin receptor antagonist/inverse agonists as antiobesity agents. After the discovery of the ghrelin peptidic antagonist [d-Lys3]GHRP-6, able to reduce food intake and BW gain in lean, ob/ob (leptin-deficient) and DIO mice, several classes of nonpeptidic ghrelin receptor antagonists [75,76] showed promising in vivo activities as antiobesity agents (preclinical researches) [75]. However, results obtained in the presence of some ghrelin antagonists/inverse agonists showed that the effect on BW and feeding not always correlates with the in vitro actions on ghrelin receptor.…”

Section: Ghrelin Antagonists/inverse Agonistsmentioning

confidence: 99%

New Perspectives on the Development of Antiobesity Drugs

Costantino

Barlocco

2015

Future Med. Chem.

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After many years of research, obesity is still a disease with an unmet medical need. Very few compounds have been approved, acting mainly on neuromediators; researches, in recent years, pointed toward compounds potentially safer than first-generation antiobesity drugs, able to interact with one or more (multitarget therapy) receptors for substances produced by the gut, adipose tissue and other targets outside CNS. Other holistic approaches, such as those involving gut microbiota and plant extracts, appeared recently in the literature, and undoubtedly will contribute to the discovery of a valuable therapy for this disease. This review deals with the positive results and the pitfalls obtained following these approaches, with a view on their clinical trial studies.

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“…Recently, the attention of researchers has turned to the development of antagonists and inverse agonists for the pharmacological treatment of obesity . However, the number of antagonists and inverse agonists revealed in the literature is much smaller compared to agonists …”

Section: Introductionmentioning

confidence: 99%

“…4,5 However, the number of antagonists and inverse agonists revealed in the literature is much smaller compared to agonists. 4,6 After almost 20 years after the discovery of endogenous ligand, no specific GHSR-1a targeting anti-obesity drug or cachexia therapeutic has reached the market for clinical use. 7 As the knowledge about ghrelin and its receptor has increased, they are no longer considered as merely protagonists in feeding initiation and GH release.…”

Section: Introductionmentioning

confidence: 99%

Peptide mimetic of N‐terminal ghrelin enhances ghrelin‐induced growth hormone secretion and c‐Fos expression in mice

Lunder

Vodnik

Kubale

et al. 2018

J Neuroendocrinology

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Orexigenic peptide ghrelin and its receptor have been extensively investigated as potential therapeutic targets, primarily because of their role in feeding initiation and growth hormone (GH) release. However, no specific ghrelin targeting anti‐obesity or cachexia therapeutics are available for clinical use thus far and further efforts in this direction are warranted. The present study aimed to find new peptide drug leads modulating ghrelin signal transduction. By targeting neutralising antibodies against ghrelin with phage display libraries, we aimed to identify peptides binding to the cognate receptor. Four synthetic peptides were selected and tested using calcium screening assays. The most effective competitive antagonist FSFLPPE was further tested in vivo. Administration of the peptide produced no significant effect on either food intake or GH release. Surprisingly, when co‐administered with ghrelin, the peptide significantly enhanced GH secretion and c‐Fos expression. The evidence obtained in the present study indicates that FSFLPPE might act as an ago‐allosteric modulator.

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Ghrelin receptor modulators: a patent review (2011 – 2014)

Cited by 9 publications

References 80 publications

Ghrelin Receptor Antagonism of Methamphetamine-Induced Conditioned Place Preference and Intravenous Self-Administration in Rats

Ghrelin Receptor Antagonism of Methamphetamine-Induced Conditioned Place Preference and Intravenous Self-Administration in Rats

New Perspectives on the Development of Antiobesity Drugs

Peptide mimetic of N‐terminal ghrelin enhances ghrelin‐induced growth hormone secretion and c‐Fos expression in mice

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