DIMERIZATION OF SUMATRIPTAN AS AN EFFICIENT WAY TO DESIGN A POTENT, CENTRALLY AND ORALLY-ACTIVE 5-HT1B AGONIST

A new bivalent ligand of formula 3 which results from the covalent cou pling of two sumatriptan molecules with a p-xylyl spacer at the level of the sulfonamide nitrogen has been prepared and evaluated as a 5-HT1 B/1D receptors agonist. In vitro experiments at 5-HT1B human cloned re ceptors (Ki = 0.64 nM; EC50 = 0.58 nM) and at the level of the contrac tion of the New Zealand white rabbit saphenous vein (pD(2) = 6.6) demo nstrate the superior potency of dimer 3 as a 5-HT1B receptor agonist w hen compared to sumatriptan or zolmitriptan. Interestingly enough, the new bivalent agonist 3 was found to induce hypothermia in the guineap ig upon oral administration suggesting good oral activity and access t o the brain. (C) 1998 Elsevier Science Ltd. All rights reserved.