Ma. Petty et al., THE SELECTIVITY OF MDL-74,721 IN MODELS OF NEUROGENIC VERSUS VASCULARCOMPONENTS OF MIGRAINE, European journal of pharmacology, 336(2-3), 1997, pp. 127-136
MDL 74,721 aminosulfonylmethyl-1,2,3,4-tetrahydronaphthalene, a sulfon
amidotetralin, has been found to exhibit a 10000-fold greater potency
in neurogenic versus vascular models of migraine. Sumatriptan, a relat
ively pure 5-HT1D/5-HT1B receptor agonist, also showed higher potency
versus neurogenic inflammation. However, for sumatriptan the potency d
ifference (100-fold) in the two pathophysiological models was less pro
nounced than seen for MDL 74,721. The affinity profile of MDL 74,721 a
t 5-HT1 receptor subtypes may in part explain its ability to different
iate these two physiological responses. MDL 74,721 demonstrated nanomo
lar affinity for 5-HT1A (12.7 +/- 0.3 nM) and 5-HT1D (41.3 +/- 10.9 nM
) but considerably lower affinity for 5-HT1B receptors (>1000 nM). Ser
otonin-like activity was seen in in vitro functional assays including
inhibition of forskolin-stimulated cAMP accumulation in human 5-HT1D r
eceptor-transfected fibroblasts or eliciting vasoconstriction in isola
ted human pial arteries. The intrinsic activity (relative to 5-HTEAmax
) and affinity (pD(2)) for the human cerebrovascular 5-HT receptors we
re: 5-HT (100%, 7.51 +/- 0.49), sumatriptan (94%, 6.85 +/- 0.1) and MD
L 74,721 (66%, 5.70 +/- 0.23), In anaesthetised cats, treatment with M
DL 74,721 resulted in a dose-related reduction in the percentage of ca
rotid flow going through the arteriovenous anastomoses to the lungs, w
ith an ED50 of 0.3 mg/kg i.v., the same as sumatriptan. However, in th
e guinea-pig neurogenic model, MDL 74,721 inhibited plasma protein ext
ravasation with an ED50 of 0.023 mu g/kg compared to 2.5 mu g/kg for s
umatriptan. MDL 74,721 was also effective in this model (in rats) afte
r oral administration. In conclusion, MDL 74,721 demonstrates a precli
nical profile consistent with anti-migraine efficacy, Its marked prefe
rence for inhibiting neurogenic inflammation makes this compound a use
ful tool for assessing the relative contribution of this pathophysiolo
gical mechanism to the human disease state. (C) 1997 Elsevier Science
B.V.