Dimerization of sumatriptan as an efficient way to design a potent, centrally and orally active 5-HT1B agonist

Bioorg Med Chem Lett. 1998 Mar 17;8(6):675-80. doi: 10.1016/s0960-894x(98)00090-0.

Abstract

A new bivalent ligand of formula 3 which results from the covalent coupling of two sumatriptan molecules with a p-xylyl spacer at the level of the sulfonamide nitrogen has been prepared and evaluated as a 5-HT1B/1D receptors agonist. In vitro experiments at 5-HT1B human cloned receptors (Ki = 0.64 nM; EC50 = 0.58 nM) and at the level of the contraction of the New Zealand white rabbit saphenous vein (pD2 = 6.6) demonstrate the superior potency of dimer 3 as a 5-HT1B receptor agonist when compared to sumatriptan or zolmitriptan. Interestingly enough, the new bivalent agonist 3 was found to induce hypothermia in the guineapig upon oral administration suggesting good oral activity and access to the brain.

MeSH terms

  • Animals
  • Cell Line
  • Dimerization
  • Drug Design*
  • Guinea Pigs
  • Humans
  • Models, Chemical
  • Rabbits
  • Receptor, Serotonin, 5-HT1B
  • Receptors, Serotonin / metabolism*
  • Serotonin Receptor Agonists / chemical synthesis*
  • Sumatriptan / chemical synthesis*

Substances

  • HTR1B protein, human
  • Receptor, Serotonin, 5-HT1B
  • Receptors, Serotonin
  • Serotonin Receptor Agonists
  • Sumatriptan