How Selective Is GR 43175? Interactions With Functional 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D Receptors

Naunyn Schmiedebergs Arch Pharmacol. 1989 Jul;340(1):135-8. doi: 10.1007/BF00169219.

Abstract

GR 43175 (3-[2-dimethylamino]ethyl-N-methyl-1 H-indole-5 methane sulphonamide) is a novel 5-HT1-like receptor-selective agonist which was reported to be active in the treatment of migraine attacks. The effects of the compound were investigated in radioligand binding studies and in functional models for 5-HT1A, 5-HT1B, and 5-HT1D receptors (inhibition of forskolin-stimulated adenylate cyclase activity in calf hippocampus, rat and calf substantia nigra, respectively) and 5-HT1C receptors (stimulation of inositol phosphate production in pig choroid plexus). GR 43175 displayed the following order of affinity for 5-HT recognition sites (pKD values, -log mol/l, in parentheses): 5-HT1D (7.54) greater than 5-HT1B (6.35) greater than 5-HT1A (6.13) much greater than 5-HT1C (4.13) greater than 5-HT2 (3.67). The same order of potency was observed at functional 5-HT1 receptors, at which GR 43175 acted as a full agonist, with the exception of the 5-HT1C receptor, where the compound was a weak antagonist (pEC50 or pKB values, -log mol/l, in parentheses): 5-HT1D (6.28) greater than 5-HT1B (6.03) greater than 5-HT1A (5.57) much greater than 5-HT1C (4.25). The present data show that GR 43175 interacts preferentially as an agonist with 5-HT1B and 5-HT1D receptors. Since 5-HT1B receptors have not yet been identified in human brain, it seems possible that it is the 5-HT1D receptor which is relevant to the reported antimigraine effects of this compound.

MeSH terms

  • Animals
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • In Vitro Techniques
  • Indoles / pharmacology*
  • Male
  • Models, Biological
  • Radioligand Assay
  • Rats
  • Receptors, Serotonin / drug effects*
  • Second Messenger Systems / drug effects
  • Serotonin / metabolism
  • Sulfonamides / pharmacology*
  • Sumatriptan
  • Swine

Substances

  • Indoles
  • Receptors, Serotonin
  • Sulfonamides
  • Serotonin
  • Sumatriptan