title: Assessment of the pharmacological properties of 5-methoxyindole derivatives at 5-HT4 receptors.
abstract: OBJECTIVE
  The aim was to examine the biological activity of 5-methoxytryptamine derivatives at the 5-hydroxytryptamine (5-HT)(4) receptor to explore the effect of substitution on the aliphatic amine of the 5-methoxyamine scaffold.
  
  
  METHODS
  Three compounds were tested for affinity at the 5-HT(4) receptor by radioligand binding and functional activity using guinea-pig ileum and human colon circular muscle preparations and also in the mouse whole gut transit test.
  
  
  RESULTS
  The three compounds all had agonist properties at the 5-HT(4) receptor but their efficacy differed in the different functional tests. Compound 3 had the highest affinity for the 5-HT(4) receptor and was a full agonist at relaxing human colon circular muscle with efficacy closest to 5-HT. Compounds 1 and 2 were partial agonists in this assay with lower efficacies; compound 2 was a full agonist in the guinea-pig ileum assay whereas compound 3 was a partial agonist. Compounds 1 and 2 also showed activity in the mouse gut transit assay while compound 3 had no activity.
  
  
  CONCLUSIONS
  Of the compounds tested, compound 3 was the most promising 5-HT(4) receptor agonist and the results highlight the value of using human tissue in functional tests when assessing compounds for potential activity.
authors: Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville Campus, Parkville, Vic., Australia.
authors: Ian M
authors: IM
authors: Coupar
authors: Helen R
authors: HR
authors: Irving
authors: David T
authors: DT
authors: Manallack
authors: Yean Y
authors: YY
authors: Tan
authors: Fadi
authors: F
authors: Ayad
authors: Juliana Di
authors: JD
authors: Iulio
authors: Nathalie
authors: N
authors: Tochon-Danguy
authors: Magdy N
authors: MN
authors: Iskander
mesh_terms: D008735:5-Methoxytryptamine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D003106:Colon / Q000187:drug effects*; D005260:Female; D005772:Gastrointestinal Transit / Q000187:drug effects; D006168:Guinea Pigs; D006801:Humans; D006898:Hydroxylamines / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects*; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*
chemical_list: D006898:Hydroxylamines; D007211:Indoles; D044422:Receptors, Serotonin, 5-HT4; D008735:5-Methoxytryptamine; C005214:methoxyamine; C487413:5-methoxyindole