title: Semagacestat, a γ-secretase inhibitor, activates the growth hormone secretagogue (GHS-R1a) receptor.
abstract: OBJECTIVE
  Semagacestat, is a γ-secretase inhibitor, which belongs to a class of drugs that are being developed as therapeutic agents for Alzheimer's disease (AD). This study aims to evaluate another potential effect of semagacestat, namely its ability to stimulate the growth hormone secretagogue receptor (GHS-R1a), which may also contribute to its therapeutic efficacy.
  
  
  METHODS
  The GHS-R1a-activating potential of semagacestat and its synthetic precursor was assessed in an in vitro calcium mobilization assay in cells expressing the GHS-R1a receptor and compared with that of the endogenous peptide GHS-R1a agonist, acyl-ghrelin, as well as the non-peptidyl synthetic GHS-R1a agonist, MK0677. In addition, semagacestat-mediated cellular trafficking of the GHS-R1a receptor, expressed as an enhanced green fluorescent protein tagged fusion protein, was analysed.
  
  
  RESULTS
  Semagacestat and its precursor were shown to activate the GHS-R1a receptor, as demonstrated by an increased GHS-R1a-mediated intracellular calcium influx. Moreover, a synergistic GHS-R1a receptor activation was shown following a combined exposure to ghrelin and semagacestat. In addition, GHS-R1a receptor internalization was observed upon exposure to semagacestat and its precursor.
  
  
  CONCLUSIONS
  These data suggest a novel molecular mechanism of action for semagacestat via modest GHS-R1a receptor activation. Studies focusing on the relative functional consequence of such effects in vivo are now warranted.
authors.affiliation: Food for Health Ireland and School of Pharmacy, University College Cork, Cork, Ireland.
authors.forename: Harriët
authors.initials: H
authors.lastname: Schellekens
authors.forename: Orla
authors.initials: O
authors.lastname: McNamara
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Dinan
authors.forename: Justin V
authors.initials: JV
authors.lastname: McCarthy
authors.forename: Gerard P
authors.initials: GP
authors.lastname: McGlacken
authors.forename: John F
authors.initials: JF
authors.lastname: Cryan
mesh_terms: D000215:Acylation; D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D001381:Azepines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D054439:Ghrelin / Q000031:analogs & derivatives / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D018697:Nootropic Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D054440:Receptors, Ghrelin / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000819:agonists / Q000378:metabolism; D013141:Spiro Compounds / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D001381:Azepines; D004791:Enzyme Inhibitors; D054439:Ghrelin; D007211:Indoles; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D018697:Nootropic Agents; D011355:Prodrugs; D054440:Receptors, Ghrelin; D011993:Recombinant Fusion Proteins; D013141:Spiro Compounds; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D053829:Amyloid Precursor Protein Secretases; D000409:Alanine; C094817:ibutamoren mesylate