Recently, several novel approaches to the treatment of
migraine have been advanced, including selective
5-hydroxytryptamine (or
serotonin) 1B/1D (5-HT(1B/1D)) receptor agonists such as
sumatriptan and
5-HT(1F) receptor agonists such as
LY344864. Many 5-HT(1B/1D) receptor agonists have been identified based on their ability to produce cerebral vascular contraction, whereas
LY344864 was identified as an inhibitor of trigeminal nerve-mediated dural extravasation. In our study, several
triptan derivatives were compared with
LY344864 for their ability to contract the rabbit saphenous vein, a tissue used in the preclinical identification of
sumatriptan-related agonists.
Sumatriptan,
zolmitriptan,
rizatriptan, and
naratriptan all contracted the rabbit saphenous vein from baseline tone, whereas
LY344864 in concentrations up to 10(-4) M did not contract the rabbit saphenous vein. Furthermore, vascular contractions to
sumatriptan were markedly augmented in the presence of
prostaglandin F(2alpha) (
PGF(2alpha)). However, even in the presence of
PGF(2alpha) (3 x 10(-7) M),
LY344864 did not contract the rabbit saphenous vein in concentrations well in excess of its
5-HT(1F) receptor affinity (pK(i) = 8.2). Only when concentrations exceeded those likely to activate 5-HT(1B) and 5-HT(1D) receptors (>10(-5) M) did modest contractile responses occur in the presence of
PGF(2alpha). Use of these
serotonergic agonists revealed a significant correlation between the contractile potency in the rabbit saphenous vein and the affinities of these agonists at 5-HT(1B) and 5-HT(1D) receptors, although contractile agonist potencies were not quantitatively similar to 5-HT(1B) or
5-HT(1D) receptor affinities. In contrast, no significant correlation existed between the contractile potencies of these
serotonergic agonists in the rabbit saphenous vein and their affinity at 5-HT(1F) receptors. These data support the contention that activation of 5-HT(1F) receptors will not result in vascular contractile effects.