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 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.
Perez
M
M
Medicinal Chemistry Division, Centre de Recherche Pierre FABRE, Castres, France.
Pauwels
P J
PJ
Fourrier
C
C
Chopin
P
P
Valentin
J P
JP
John
G W
GW
Marien
M
M
Halazy
S
S
D000818:Animals; D002460:Cell Line; D019281:Dimerization; D015195:Drug Design; D006168:Guinea Pigs; D006801:Humans; D008956:Models, Chemical; D011817:Rabbits; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis*; D018170:Sumatriptan / Q000138:chemical synthesis*
C470302:HTR1B protein, human; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D018170:Sumatriptan