Identification of new gonadotrophin-releasing hormone partial agonists

Leaños‐Miranda, Alfredo; Ulloa‐Aguirre, Alfredo; Cervini, Laura; Rivier, Jean; Conn, P. Michael

doi:10.1677/joe.1.06724

Cited by 4 publications

(3 citation statements)

References 51 publications

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“…The dose-response curve fitted to the mean data from seven different slices (one slice per animal) gave an ED 50 = 0.56 n M . This value is similar to that obtained by measuring GnRH-stimulated inositol phosphate production in cultured COS-7 cells expressing the rat GnRH receptor (ED 50 = 1.5 ± 0.48 n M [23]), and LH release from cultured pituitary cells from ovariectomized adult female rats (ED 50 ∼0.7 n M [24]), and the number of LH-secreting cells in pituitary cultures from metestrous rats (ED 50 ∼ 0.8 n M [2]). When dose-response curves from different pituitaries are compared, they can be divided in two groups: a high affinity group (mean ED 50 = 0.39 n M ) and a low affinity group (mean ED 50 = 2.35 n M ).…”

Section: Discussionsupporting

confidence: 84%

GnRH-Induced [Ca2+]i-Signalling Patterns in Mouse Gonadotrophs Recorded from Acute Pituitary Slices in vitro

Sánchez-Cárdenas

Hernández‐Cruz²

2010

Neuroendocrinology

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In this study we used [Ca²⁺]_i imaging to monitor GnRH-induced intracellular Ca²⁺ signalling from dozens of gonadotrophs in mouse male pituitary slices. Responses of individual cells vary in magnitude, latency, duration and frequency of oscillation. Approximately 20% of gonadotrophs in situ display Ca²⁺ oscillations of increasing frequency at higher [GnRH] and biphasic (peak-plateau) responses at saturating [GnRH]. Nevertheless, this orderly progression, reported in cultured cells, is less well organized in 55% of cells. Furthermore, approximately 30% cells display non-oscillatory GnRH responses, reminiscent of immature gonadotrophs. Dose-response curves of slices from different animals suggest inter-individual differences in GnRH sensitivity. When the same dose of GnRH is applied repeatedly, individual cell responses are almost identical both in latency, oscillatory pattern and duration resembling the ‘Ca²⁺ fingerprint’ phenomenon. In addition, gonadotrophs in situare arranged in small clusters with similar GnRH-induced intracellular Ca²⁺-signalling patterns. Neighbouring gonadotrophs within clusters often display synchronized GnRH-induced responses with high correlation indices (>0.75). Nevertheless, synchronized responses between pairs of gonadotrophs are unaffected by incubation with blockers of gap-junction channels or P2X receptor channels, suggesting that they are not mediated by gap junctions or ATP. Alternative explanations are discussed, including pseudo-synchronization. In summary, while gonadotrophs in situ display GnRH-induced responses similar to those observed in cultured cells, different patterns and novel aspects of functional organization were found which deserve further investigation. This study on GnRH-induced Ca²⁺ signalling in the acute mice pituitary gland might be of potential relevance for characterizing GnRH actions in gonadotrophs in transgenic and knockout animals.

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Section: Discussionsupporting

confidence: 84%

GnRH-Induced [Ca2+]i-Signalling Patterns in Mouse Gonadotrophs Recorded from Acute Pituitary Slices in vitro

Sánchez-Cárdenas

Hernández‐Cruz²

2010

Neuroendocrinology

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“…This antagonist blocks GnRH and inhibits LH production, which in turn causes a suppression of testosterone and DHT [41,68]. In addition, other antagonistic peptide analogues such as Antide [N-Ac-DNal 1 , DpClPhe 2 , DPal 3 , Lys(Nic) 5 , DLys(Nic) 6 , Lys(iPr) 8 Rivier et al have designed and synthesized a large number of modified GnRH analogues, both agonistic [69] and antagonistic [70][71][72][73], using unnatural amino acids [74,75], cyclization and in some cases dicyclization [76][77][78][79]. Variable substitutions were involved in almost all positions, especially in the N-terminal, leading to the synthesis of antagonists [80][81][82].…”

Section: Nhmentioning

confidence: 99%

Peptides as Therapeutic Agents or Drug Leads for Autoimmune, Hormone Dependent and Cardiovascular Diseases

Mantzourani¹,

Laimou²,

Matsoukas³

et al. 2008

AIAAMC

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Peptides regulate most physiological processes, mainly by binding to specific receptors located on the cell surface and inducing a series of signals, neurotransmissions or the release of growth factors. There has been a rapid expansion in the use of peptides as therapeutic agents after the 1960s, but a series of unfortunate side effects present in Phase I and II clinical studies combined with their low bioavailability, led to the introduction of the idea of peptidomimetics as alternative compounds that mimic the biological activity of peptides, while offering the advantages of increased bioavailability, biostability, bioefficiency, and bioselectivity. Since then new peptides with promising in vitro results, involving the monoclonal antibody expansion, as well as the newly launched research field for novel formulations for increasing peptides' bioavailability, redirected the interest on the peptide market. In this report we will highlight three areas where the use of peptides has shown promising results, with products that are either currently used as drugs or included into Phase III clinical studies.

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“…In the literature, the term is also used for agonists that are endowed with higher binding affinity compared with the endogenous activator. For example, ‘superagonists’ of the gonadotropin‐releasing hormone receptor, such as the synthetic nonapeptide buserelin, have usually higher biological potency but not necessarily higher efficacy than the endogenous agonist gonadotropin‐releasing hormone (Loumaye et al ., ; Padula, ; Leaños‐Miranda et al ., ). However, more‐than‐physiological receptor binding does not necessarily accompany more‐than‐physiological efficacy for receptor activation.…”

Section: Classification Of Gpcr Ligands In the Light Of The Term ‘Supmentioning

confidence: 97%

Superagonism at G protein‐coupled receptors and beyond

Schrage

Min

Hochheiser

et al. 2015

British J Pharmacology

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Ligands targeting GPCRs can be categorized according to their intrinsic efficacy to trigger a specific, receptor-mediated response. A ligand endowed with the same level of efficacy as the endogenous agonist can be classified as a full agonist, whereas a compound that displays greater efficacy, that is, higher receptor signalling output than the endogenous agonist, can be called a superagonist. Subsequent to GPCR activation, an intracellular signalling cascade is set in motion, which may generate substantial amplification of the signal. This may obscure superagonism in pharmacological assays and, therefore, the definition of superagonism necessitates a combination of operational approaches, reduction of spare receptors or estimation of receptor activation close to the receptor level to quantify relative agonist efficacies in a particular system. The first part of this review will compare GPCR superagonism with superagonism in the field of immunology, where this term is well established. In the second part, known GPCR superagonists will be reviewed. Then, the experimental and analytical challenges in the deconvolution of GPCR superagonism will be addressed. Finally, the potential benefit of superagonism is discussed. The molecular mechanisms behind GPCR superagonism are not completely understood. However, crystallography shows that agonist binding alone is not sufficient for a fully active receptor state and that binding of the G protein is at least equally important. Accordingly, the emerging number of reported superagonists implies that ligand-induced receptor conformations more active than the ones stabilized by the endogenous agonist are indeed feasible. Superagonists may have therapeutic potential when receptor function is impaired or to induce negative feedback mechanisms. LINKED ARTICLES

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Identification of new gonadotrophin-releasing hormone partial agonists

Cited by 4 publications

References 51 publications

GnRH-Induced [Ca2+]i-Signalling Patterns in Mouse Gonadotrophs Recorded from Acute Pituitary Slices in vitro

GnRH-Induced [Ca2+]i-Signalling Patterns in Mouse Gonadotrophs Recorded from Acute Pituitary Slices in vitro

Peptides as Therapeutic Agents or Drug Leads for Autoimmune, Hormone Dependent and Cardiovascular Diseases

Superagonism at G protein‐coupled receptors and beyond

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