Growth Hormone Secretagogues

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Antonio Torsello - One of the best experts on this subject based on the ideXlab platform.

  • Growth Hormone Secretagogues and the regulation of calcium signaling in muscle
    International Journal of Molecular Sciences, 2019
    Co-Authors: Elena Bresciani, Vittorio Locatelli, Laura Rizzi, Silvia Coco, Laura Molteni, Ramona Meanti, Antonio Torsello
    Abstract:

    Growth Hormone Secretagogues (GHS) are a family of synthetic molecules, first discovered in the late 1970s for their ability to stimulate Growth Hormone (GH) release. Many effects of GHS are mediated by binding to GHS-R1a, the receptor for the endogenous Hormone ghrelin, a 28-amino acid peptide isolated from the stomach. Besides endocrine functions, both ghrelin and GHS are endowed with some relevant extraendocrine properties, including stimulation of food intake, anticonvulsant and anti-inflammatory effects, and protection of muscle tissue in different pathological conditions. In particular, ghrelin and GHS inhibit cardiomyocyte and endothelial cell apoptosis and improve cardiac left ventricular function during ischemia–reperfusion injury. Moreover, in a model of cisplatin-induced cachexia, GHS protect skeletal muscle from mitochondrial damage and improve lean mass recovery. Most of these effects are mediated by GHS ability to preserve intracellular Ca2+ homeostasis. In this review, we address the muscle-specific protective effects of GHS mediated by Ca2+ regulation, but also highlight recent findings of their therapeutic potential in pathological conditions characterized by skeletal or cardiac muscle impairment.

  • protective but not anticonvulsant effects of ghrelin and jmv 1843 in the pilocarpine model of status epilepticus
    PLOS ONE, 2013
    Co-Authors: Chiara Lucchi, Giulia Curia, Vittorio Locatelli, Elena Bresciani, Fabio Gualtieri, Antonio Torsello, Giuseppe Biagini, Jonathan Vinet
    Abstract:

    In models of status epilepticus ghrelin displays neuroprotective effects mediated by the Growth Hormone secretagogue-receptor 1a (GHS-R1a). This activity may be explained by anticonvulsant properties that, however, are controversial. We further investigated neuroprotection and the effects on seizures by comparing ghrelin with a more effective GHS-R1a agonist, JMV-1843. Rats were treated either with ghrelin, JMV-1843 or saline 10 min before pilocarpine, which was used to induce status epilepticus. Status epilepticus, developed in all rats, was attenuated by diazepam. No differences were observed among the various groups in the characteristics of pilocarpine-induced seizures. In saline group the area of lesion, characterized by lack of glial fibrillary acidic protein immunoreactivity, was of 0.45±0.07 mm2 in the hippocampal stratum lacunosum-moleculare, and was accompanied by upregulation of laminin immunostaining, and by increased endothelin-1 expression. Both ghrelin (P<0.05) and JMV-1843 (P<0.01) were able to reduce the area of loss in glial fibrillary acidic protein immunostaining. In addition, JMV-1843 counteracted (P<0.05) the changes in laminin and endothelin-1 expression, both increased in ghrelin-treated rats. JMV-1843 was able to ameliorate neuronal survival in the hilus of dentate gyrus and medial entorhinal cortex layer III (P<0.05 vs saline and ghrelin groups). These results demonstrate diverse protective effects of Growth Hormone Secretagogues in rats exposed to status epilepticus.

  • Growth Hormone Secretagogues exert differential effects on skeletal muscle calcium homeostasis in male rats depending on the peptidyl nonpeptidyl structure
    Endocrinology, 2013
    Co-Authors: Antonella Liantonio, Antonio Torsello, Laura Rizzi, Sabata Pierno, Bodvael Fraysse, Gianluca Gramegna, Giuseppe Carbonara, Valeriana Sblendorio, Viviana Giannuzzi, Diana Conte Camerino
    Abstract:

    The orexigenic and anabolic effects induced by ghrelin and the synthetic GH Secretagogues (GHSs) are thought to positively contribute to therapeutic approaches and the adjunct treatment of a number of diseases associated with muscle wasting such as cachexia and sarcopenia. However, many questions about the potential utility and safety of GHSs in both therapy and skeletal muscle function remain unanswered. By using fura-2 cytofluorimetric technique, we determined the acute effects of ghrelin, as well as of peptidyl and nonpeptidyl synthetic GHSs on calcium homeostasis, a critical biomarker of muscle function, in isolated tendon-to-tendon male rat skeletal muscle fibers. The synthetic nonpeptidyl GHSs, but not peptidyl ghrelin and hexarelin, were able to significantly increase resting cytosolic calcium [Ca2+]i. The nonpeptidyl GHS-induced [Ca2+]i increase was independent of GHS-receptor 1a but was antagonized by both thapsigargin/caffeine and cyclosporine A, indicating the involvement of the sarcoplasmic re...

  • novel domain selective ace inhibiting activity of synthetic Growth Hormone Secretagogues
    Pharmacological Research, 2012
    Co-Authors: Antonio Torsello, Elena Bresciani, Laura Rizzi, Monica Ravelli, I Bulgarelli, G Ricci, Barbara Ghiazza, Marina Del Puppo, Veronica Mainini, Robert J Omeljaniuk
    Abstract:

    The mechanisms of cardiovascular protective effects of ghrelin and its synthetic analogs are still largely unknown. Our first aim was to ascertain whether or not natural and synthetic ligands of GHS-R1a are capable of interfering with the activity of the renin-angiotensin system. Second, since polymorphisms in the ACE gene have been associated with Alzheimer's dementia (AD) and ACE is potentially involved in brain β-amyloid degradation, we also investigated the state of ghrelin axis and inflammatory markers in patients with AD and vascular dementia (VaD). Desacyl ghrelin, hexarelin, EP80317, and GHRP-6 all significantly inhibited ACE activity in vitro; by comparison, the efficacies of ghrelin and MK-0677 were significantly lower, suggesting that ACE-inhibiting activity is unrelated to ligand affinity to GHS-R1a. ACE was capable of cleaving Aβin vitro, reducing its ability to aggregate in fibrillar Aβ. Interestingly, this protective effect of ACE was blunted by enalapril but not hexarelin or EP80317. Desacyl ghrelin levels were lower in VaD subjects compared with AD and control subjects, whereas ghrelin and TNF-α levels were similar in all groups. VaD subjects demonstrated greater levels of mRNA for GHS-R1a, PPAR-γ and CD36 in peripheral blood lymphocytes compared with other groups. In conclusion, some GHSs are effective ACE-inhibitors, and this activity may contribute to their cardiovascular effects. Hexarelin or EP80317 do not inhibit the N-domain of ACE, which is also involved in the metabolism of β-amyloid, suggesting the possibility of developing new antihypertensive drugs with improved therapeutic potential.

  • new active series of Growth Hormone Secretagogues
    Journal of Medicinal Chemistry, 2003
    Co-Authors: Vincent Guerlavais, Vittorio Locatelli, Antonio Torsello, Romano Deghenghi, Corrado Ghe, Damien Boeglin, Delphine Mousseaux, Catherine Oiry, Annie Heitz, Filomena Catapano
    Abstract:

    New Growth Hormone secretagogue (GHS) analogues were synthesized and evaluated for Growth Hormone releasing activity. This series derived from EP-51389 is based on a gem-diamino structure. Compounds that exhibited higher in vivo GH-releasing potency than hexarelin in rat (subcutaneous administration) were then tested per os in beagle dogs and for their binding affinity to human pituitary GHS receptors and to hGHS-R 1a. Compound 7 (JMV 1843, H-Aib-(d)-Trp-(d)-gTrp-formyl) showed high potency in these tests and was selected for clinical studies.(1)

Roy G Smith - One of the best experts on this subject based on the ideXlab platform.

  • potent 3 spiropiperidine Growth Hormone Secretagogues
    ChemInform, 2010
    Co-Authors: Lihu Yang, Greg Morriello, Kristine Prendergast, Kang Cheng, Roy G Smith, Thomas M. Jacks, Klaus D. Schleim, Wanda Chan, Arthur A. Patchett
    Abstract:

    Systematic SAR studies of the different regioisomers and homologues of the spiro(indane-1,4-piperidine) moiety in the Growth Hormone secretagogue L-162,752 are presented. Among them, spiro(3H-1-benzopyran-2,3-piperidine) was found to afford Secretagogues with low nanomolar in vitro activity.

  • development of Growth Hormone Secretagogues
    Endocrine Reviews, 2005
    Co-Authors: Roy G Smith
    Abstract:

    The GH Secretagogues (GHS) were developed by reverse pharmacology. The objective was to develop small molecules with pharmacokinetics suitable for once-daily oral administration that would rejuvenate the GH/IGF-I axis. Neither the receptor nor the ligand that controlled pulse amplitude of Hormone release was known; therefore, identification of lead structures was based on function. I reasoned that GH pulse amplitude could be increased by four possible mechanisms: 1) increasing GHRH release; 2) amplifying GHRH signaling in somatotrophs of the anterior pituitary gland; 3) reducing somatostatin release; and 4) antagonizing somatostatin receptor signaling. Remarkably, the GHS act through all four mechanisms to reproduce a young adult physiological GH profile in elderly subjects that was accompanied by increased bone mineral density and lean mass, modest improvements in strength, and improved recovery from hip fracture. Furthermore, restoration of thymic function was induced in old mice. The GHS receptor (GHS-R) was subsequently identified by expression cloning and found to be a previously unknown G protein-coupled receptor expressed predominantly in brain, pituitary gland, and pancreas. Reverse pharmacology was completed when the cloned GHS-R was exploited to identify an endogenous agonist (ghrelin) and a partial agonist (adenosine); ghsr-knockout mice studies confirmed that GHS are ghrelin mimetics.

  • Growth Hormone Secretagogues prospects and potential pitfalls
    Best Practice & Research Clinical Endocrinology & Metabolism, 2004
    Co-Authors: Roy G Smith, Yuxiang Sun, Lorena Betancourt, Mark Asnicar
    Abstract:

    Abstract The Growth Hormone Secretagogues (GHSs) are the first well-characterised agents that rejuvenate the Growth Hormone (GH)/insulin-like Growth factor (IGF-1) axis. This property was discovered during investigations of the underlying causative mechanisms of age-related endocrine changes. Chronic administration of the long acting GHS, MK-0677, reverses the age-related decline in pulse-amplitude of GH secretion and restores IGF-1 levels producing profiles typical of young adults. This restoration is accompanied by improvements in body composition in frail elderly subjects. When given acutely, the GHSs also increase appetite. Following cloning and characterisation of the GHS-receptor (GHS-R) an endogenous ligand, ghrelin, was isolated and identified. Ghrelin shares the GH releasing and orexigenic properties of the GHSs. Studies using Ghsr -null mice confirmed that the GHS-R was the ghrelin-receptor; hence, the GHSs should be considered to be ‘ghrelin mimetics.' Ghrelin levels are reported to decline during ageing, therefore long-acting GHSs are ideal candidates for ghrelin replacement therapy.

  • Growth Hormone Secretagogues modulate the electrical and contractile properties of rat skeletal muscle through a ghrelin specific receptor
    British Journal of Pharmacology, 2003
    Co-Authors: Sabata Pierno, Roy G Smith, Annamaria De Luca, Jeanfrancois Desaphy, Bodvael Fraysse, Antonella Liantonio, Maria Paola Didonna, M D Lograno, Daniela Cocchi, Diana Conte Camerino
    Abstract:

    (1) Growth Hormone Secretagogues (GHS) exhibit potent Growth Hormone (GH)-releasing activity through the activation of a pituitary receptor. Here, we consider the possibility that GHS can target a specific receptor in rat skeletal muscle and have a role in the control of muscle function. (2) By means of the intracellular microelectrode technique, we found that in vitro application of hexarelin and L-163,255 dose dependently reduced resting chloride (gCl) and potassium (gK) conductances in rat skeletal muscle. These effects were prevented by the GHS-receptor antagonist [D-Lys-3]-GHRP-6, and by either phospholipase C or protein kinase C (PKC) inhibitors. Ghrelin, a natural ligand of GHS receptors, also induced a reduction of muscle gCl and gK, which was antagonised by [D-Lys-3]-GHRP-6. (3) Both GHS shifted the mechanical threshold for the contraction of muscle fibres towards more negative voltages. Accordingly, by means of FURA-2 fluorescent measurements, we demonstrated that L-163,255 induced a resting [Ca(2+)](i) increase, which was reversible and not blocked by nifedipine or removal of external Ca(2+). (4) Ageing is a condition characterised by a deficit of GH secretion, which in turn modifies the electrical and contractile properties of skeletal muscle. In contrast to GH, chronic treatment of aged rats with hexarelin or L-163,255 failed to restore the electrical and contractile muscle properties. Moreover, the two GHS applied in vitro were able to antagonise the beneficial effect on gCl and gK obtained through chronic treatment of aged animals with GH. (5) Thus, skeletal muscle expresses a specific GHS receptor able to decrease gCl and gK through a PKC-mediated intracellular pathway. This peripheral action may account for the lack of restoration of skeletal muscle function in long-term GHS-treated aged animals.

  • thiazole derived potent highly bioavailable short duration Growth Hormone Secretagogues
    ChemInform, 1999
    Co-Authors: Lihu Yang, Greg Morriello, Kang Cheng, Roy G Smith, Klaus D. Schleim, Kwan Leung, Tom Jacks, Arthur A. Patchett
    Abstract:

    Replacement of the phenyl in 3 with a 2-pyridyl or 4-thiazolyl group resulted in increased potency in the rat pituitary cell GH release assay and in beagles.

Chen Chen - One of the best experts on this subject based on the ideXlab platform.

  • 4 protective role of Growth Hormone Secretagogues against myocardial dysfunction in mouse models of myocardial ischemia reperfusion and infarction
    Heart, 2015
    Co-Authors: H Mcdonald, Nyoman D Kurniawan, Jason Nigel John Peart, Chen Chen
    Abstract:

    Growth Hormone Secretagogues (GHS) have been shown to possess cardioprotective properties in ischaemic heart disease models. This study aimed to determine whether hexarelin, a synthetic GHS, preserves cardiac function in models of myocardial infarction (MI). MI was induced by permanent ligation of the left descending coronary artery (LAD) in C57BL/6J mice (n = 44). In a second group (n = 39), the LAD was transiently ligated, followed by reperfusion. Vehicle or hexarelin was administered at 0.3 mg/kg/day subcutaneously. Treated and sham mice were subjected to magnetic resonance imaging using a T1-weighted late gadolinium enhancement sequence (LGE) at 9.4 Tesla (T) to measure ventricular function and tissue characteristics at 24 h and 21 days post-LAD ligation. Infarct size and area-at-risk was confirmed using ex-vivo analysis at 16.4T using a 3D T1/T2*-weighted sequence using iron nanoparticles and LGE. Hexarelin-treated mice demonstrated a significant improvement (P in vivo .

  • Growth Hormone Secretagogues preserve the electrophysiological properties of mouse cardiomyocytes isolated from in vitro ischemia reperfusion heart
    Endocrinology, 2012
    Co-Authors: Lin Zhang, Breadley S Launikonis, Chen Chen
    Abstract:

    Ischemic heart diseases often induce cardiac arrhythmia with irregular cardiac action potential (AP). This study aims to demonstrate that GH Secretagogues (GHS) ghrelin and its synthetic analog hexarelin can preserve the electrophysiological properties of cardiomyocytes experiencing ischemia/reperfusion (I/R). Isolated hearts from adult male mice underwent 20 min global ischemia followed by 30 min reperfusion using a Langendorff apparatus. Ghrelin (10 nm) or hexarelin (1 nm) was administered in the perfusion solution either 10 min before or after ischemia, termed pre- or posttreatments. Cardiomyocytes isolated from these hearts were used for whole-cell patch clamping to measure AP, voltage-gated L-type calcium current (ICaL), transient outward potassium current (Ito), and sodium current (INa). AP amplitude and duration were significantly decreased by I/R, but GHS treatments maintained their normality. GHS treatments prevented the decrease in ICaL and INa after I/R, thereby maintaining AP amplitude. Althou...

  • Growth Hormone Secretagogues protect mouse cardiomyocytes from in vitro ischemia reperfusion injury through regulation of intracellular calcium
    PLOS ONE, 2012
    Co-Authors: Lin Zhang, Joshua N Edwards, Breadley S Launikonis, Chen Chen
    Abstract:

    BACKGROUND Ischemic heart disease is a leading cause of mortality. To study this disease, ischemia/reperfusion (I/R) models are widely used to mimic the process of transient blockage and subsequent recovery of cardiac coronary blood supply. We aimed to determine whether the presence of the Growth Hormone Secretagogues, ghrelin and hexarelin, would protect/improve the function of heart from I/R injury and to examine the underlying mechanisms. METHODOLOGY/PRINCIPAL FINDINGS Isolated hearts from adult male mice underwent 20 min global ischemia and 30 min reperfusion using a Langendorff apparatus. Ghrelin (10 nM) or hexarelin (1 nM) was introduced into the perfusion system either 10 min before or after ischemia, termed pre- and post-treatments. In freshly isolated cardiomyocytes from these hearts, single cell shortening, intracellular calcium ([Ca(2+)](i)) transients and caffeine-releasable sarcoplasmic reticulum (SR) Ca(2+) were measured. In addition, RT-PCR and Western blots were used to examine the expression level of GHS receptor type 1a (GHS-R1a), and phosphorylated phospholamban (p-PLB), respectively. Ghrelin and hexarelin pre- or post-treatments prevented the significant reduction in the cell shortening, [Ca(2+)](i) transient amplitude and caffeine-releasable SR Ca(2+) content after I/R through recovery of p-PLB. GHS-R1a antagonists, [D-Lys3]-GHRP-6 (200 nM) and BIM28163 (100 nM), completely blocked the effects of GHS on both cell shortening and [Ca(2+)](i) transients. CONCLUSION/SIGNIFICANCE Through activation of GHS-R1a, ghrelin and hexarelin produced a positive inotropic effect on ischemic cardiomyocytes and protected them from I/R injury probably by protecting or recovering p-PLB (and therefore SR Ca(2+) content) to allow the maintenance or recovery of normal cardiac contractility. These observations provide supporting evidence for the potential therapeutic application of ghrelin and hexarelin in patients with cardiac I/R injury.

  • Growth Hormone Secretagogues reduce transient outward k current via phospholipase c protein kinase c signaling pathway in rat ventricular myocytes
    Endocrinology, 2010
    Co-Authors: Chen Chen, Qiang Sun, Weijin Zang
    Abstract:

    Endogenous ghrelin and its synthetic counterpart hexarelin are peptide GH Secretagogues (GHS) that exert a positive ionotropic effect in the cardiovascular system. The mechanism by which GHS modulate cardiac electrophysiology properties to alter myocyte contraction is poorly understood. In the present study, we examined whether GHS regulates the transient outward potassium current (Ito) as well as the putative intracellular signaling cascade responsible for such regulation. GHS and experimental agents were applied locally onto freshly isolated adult Sprague-Dawley rat ventricular myocytes and action potential morphology and Ito was recorded using nystatin-perforated whole-cell patch-clamp recording technique. Under current clamp, ghrelin and hexarelin (10 nm) significantly prolonged action potential duration. Under voltage clamp, hexarelin and ghrelin inhibited Ito in a concentration-dependent manner. This inhibition was abolished in the presence of the GHS receptor (GHS-R) antagonist [d-Lys3]GH-releasing...

  • the role of ghrelin and Growth Hormone Secretagogues receptor on rat adipogenesis
    Endocrinology, 2003
    Co-Authors: Kichoon Choi, Masayasu Kojima, Kenji Kangawa, Chen Chen, Sanggun Roh, Yeon Hee Hong, Yogendra B Shrestha, Daisuke Hishikawa, Shinichi Sasaki
    Abstract:

    Recent research progress indicates a close link between ghrelin, a natural ligand of GH Secretagogues receptor (GHS-R), and both the metabolic balance and body composition. To clarify the involvement of ghrelin and GHS-R in the process of adipogenesis, we measured the expression of GHS-R and peroxisome proliferator-activated receptor {gamma} 2 (PPAR-{gamma}2) mRNA in rat adipocytes using semiquantitative RT-PCR methods. The levels of GHS-R mRNA increased by up to 4-fold in adipose tissue from epididymal and parametrial regions as the rat aged from 4–20 wk and were significantly elevated during the differentiation of preadipocytes in vitro. Ghrelin (10-8 M for 10 d) stimulated the activity of glycerol-3-phosphate dehydrogenase and the differentiation of rat preadipocytes in vitro. Ghrelin treatment also significantly increased the levels of PPAR-{gamma}2 mRNA in primary cultured rat differentiated adipocytes. In addition, isoproterenol (10-8 M, 40 min)-stimulated lipolysis was significantly reduced by simultaneous ghrelin treatment in a dose-dependent manner in vitro. In conclusion, the expression of GHS-R in rat adipocytes increases with the age and during adipogenesis. Ghrelin in vitro stimulates the differentiation of preadipocytes and antagonizes lipolysis. Ghrelin may therefore play an important role in the process of adipogenesis in rats.

Thomas M. Jacks - One of the best experts on this subject based on the ideXlab platform.

  • potent 3 spiropiperidine Growth Hormone Secretagogues
    ChemInform, 2010
    Co-Authors: Lihu Yang, Greg Morriello, Kristine Prendergast, Kang Cheng, Roy G Smith, Thomas M. Jacks, Klaus D. Schleim, Wanda Chan, Arthur A. Patchett
    Abstract:

    Systematic SAR studies of the different regioisomers and homologues of the spiro(indane-1,4-piperidine) moiety in the Growth Hormone secretagogue L-162,752 are presented. Among them, spiro(3H-1-benzopyran-2,3-piperidine) was found to afford Secretagogues with low nanomolar in vitro activity.

  • highly potent Growth Hormone Secretagogues
    Bioorganic & Medicinal Chemistry Letters, 2007
    Co-Authors: James R. Tata, Wanda W.-s. Chan, Kang Cheng, Thomas M. Jacks, Klaus D. Schleim, Liente Wei, Bridget Butler, Gerard J Hickey, Arthur A. Patchett
    Abstract:

    Abstract During an effort to search for more potent Growth Hormone Secretagogues, we discovered a class of compounds of which the best compound 8 was 7-fold more active in vitro than the best compound in the series we revealed before [Tata, J. R.; Lu, Z.; Jacks, T. M.; Schleim, K. D.; Cheng, K.; Wei, L.; Chan, W.-S.; Butler, B.; Tsou, N.; Leung, K.; Chiu, S.-H. L.; Hickey, G. J.; Smith, R. G.; Patchett, A. A. Bioorg. Med. Chem. Lett. 1997 , 7 , 2319.]. Animal studies show that compound 8 can stimulate Growth Hormone release at the oral dose as low as 0.06 mpk. Chemistry and biological studies are discussed.

  • substituted bridged phenyl piperidines orally active Growth Hormone Secretagogues
    ChemInform, 2003
    Co-Authors: James R. Tata, Wanda W.-s. Chan, Kang Cheng, Thomas M. Jacks, Klaus D. Schleim, Liente Wei, Bridget Butler, Gerard J Hickey, Arthur A. Patchett
    Abstract:

    A new series of Growth Hormone Secretagogues have been discovered. The best compound, 26j, shows excellent ability to release Growth Hormone both in vitro and in vivo. The synthesis and biological activity of these compounds are discussed.

  • synthesis and biological activities of spiroheterocyclic Growth Hormone Secretagogues
    ChemInform, 1999
    Co-Authors: Menghsin Chen, Wanda W.-s. Chan, Arthur A. Patchett, Kang Cheng, Thomas M. Jacks, Liente Wei, Bridget Butler, Patrick P Pollard, Roy G Smith
    Abstract:

    The synthesis and biological activities of a series of spiroheterocyclic Growth Hormone Secretagogues are reported. Modification of the spiroindane part-structure of the prototypal secretagogue L-162,752 revealed that the spiroindane could be replaced with spirobenzodihydrothiophen derivatives to enhance not only in vitro potency but also oral activity. In this study non-aromatic D-2-amino-4-cyclohexylbutanoic analogs (8a-8d) were also identified to be active Secretagogues.

  • synthesis and biological activities of phenyl piperazine based peptidomimetic Growth Hormone Secretagogues
    Bioorganic & Medicinal Chemistry Letters, 1998
    Co-Authors: Khaled J Barakat, Wanda W.-s. Chan, Kang Cheng, Roy G Smith, Thomas M. Jacks, Klaus D. Schleim, Bridget Butler, Gerard J Hickey, Donald F Hora, Arthur A. Patchett
    Abstract:

    Abstract A new class of potent, orally active phenyl piperazine-based GH Secretagogues have been discovered from attempts to mimic the arrangement of the phenyl substitutent in the spiroindanyl piperidine and spiroindoline sulfonamide privileged structures of 4 and 1 , respectively. The best of these compounds, 18 (EC 50 = 2.8 nM) is nearly as potent as MK-0677 for releasing GH from rat pituitary cells.

Arthur A. Patchett - One of the best experts on this subject based on the ideXlab platform.

  • potent 3 spiropiperidine Growth Hormone Secretagogues
    ChemInform, 2010
    Co-Authors: Lihu Yang, Greg Morriello, Kristine Prendergast, Kang Cheng, Roy G Smith, Thomas M. Jacks, Klaus D. Schleim, Wanda Chan, Arthur A. Patchett
    Abstract:

    Systematic SAR studies of the different regioisomers and homologues of the spiro(indane-1,4-piperidine) moiety in the Growth Hormone secretagogue L-162,752 are presented. Among them, spiro(3H-1-benzopyran-2,3-piperidine) was found to afford Secretagogues with low nanomolar in vitro activity.

  • highly potent Growth Hormone Secretagogues
    Bioorganic & Medicinal Chemistry Letters, 2007
    Co-Authors: James R. Tata, Wanda W.-s. Chan, Kang Cheng, Thomas M. Jacks, Klaus D. Schleim, Liente Wei, Bridget Butler, Gerard J Hickey, Arthur A. Patchett
    Abstract:

    Abstract During an effort to search for more potent Growth Hormone Secretagogues, we discovered a class of compounds of which the best compound 8 was 7-fold more active in vitro than the best compound in the series we revealed before [Tata, J. R.; Lu, Z.; Jacks, T. M.; Schleim, K. D.; Cheng, K.; Wei, L.; Chan, W.-S.; Butler, B.; Tsou, N.; Leung, K.; Chiu, S.-H. L.; Hickey, G. J.; Smith, R. G.; Patchett, A. A. Bioorg. Med. Chem. Lett. 1997 , 7 , 2319.]. Animal studies show that compound 8 can stimulate Growth Hormone release at the oral dose as low as 0.06 mpk. Chemistry and biological studies are discussed.

  • substituted bridged phenyl piperidines orally active Growth Hormone Secretagogues
    ChemInform, 2003
    Co-Authors: James R. Tata, Wanda W.-s. Chan, Kang Cheng, Thomas M. Jacks, Klaus D. Schleim, Liente Wei, Bridget Butler, Gerard J Hickey, Arthur A. Patchett
    Abstract:

    A new series of Growth Hormone Secretagogues have been discovered. The best compound, 26j, shows excellent ability to release Growth Hormone both in vitro and in vivo. The synthesis and biological activity of these compounds are discussed.

  • spiro indoline 3 4 piperidine Growth Hormone Secretagogues as ghrelin mimetics
    Bioorganic & Medicinal Chemistry Letters, 2001
    Co-Authors: Brenda Palucki, Arthur A. Patchett, Karen K Mckee, Scott D Feighner, Andrew D Howard, Donna L Hreniuk, Shengshung Pong, Carina P Tan, Lex H Y Van Der Ploeg, Ravi P Nargund
    Abstract:

    A series of small molecules derived from MK-0677, a potent synthetic GHS, mimicking the N-terminal Gly-Ser-O-(n-octanoyl)-L-Ser-Phe segment of ghrelin was synthesized and tested in a binding and in a functional assay measuring intracellular calcium elevation in HEK-293 cells expressing hGHSR1a. Replacement of Phe in this tetrapeptide with a spiro(indoline-3,4'-piperidine) group, Gly-Ser with 2-aminoisobutyric acid, and O-(n-octanoyl)-L-Ser with O-benzyl-D-Ser provided synthetic GHS agonists with similar functional potency as ghrelin.

  • thiazole derived potent highly bioavailable short duration Growth Hormone Secretagogues
    ChemInform, 1999
    Co-Authors: Lihu Yang, Greg Morriello, Kang Cheng, Roy G Smith, Klaus D. Schleim, Kwan Leung, Tom Jacks, Arthur A. Patchett
    Abstract:

    Replacement of the phenyl in 3 with a 2-pyridyl or 4-thiazolyl group resulted in increased potency in the rat pituitary cell GH release assay and in beagles.

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