The selectivity of MDL 74,721 in models of neurogenic versus vascular components of migraine.
MDL 74,721 (R)-2-(N1,N1-dipropylamino)-8-methylaminosulfonylmethyl-1,2,3,4-te trahydronaphthalene, a sulfonamidotetralin, has been found to exhibit a 10,000-fold greater potency in neurogenic versus vascular models of migraine. Sumatriptan, a relatively pure 5-HT1D/5-HT1B receptor agonist, also showed higher potency versus neurogenic inflammation. However, for sumatriptan the potency difference (100-fold) in the two pathophysiological models was less pronounced than seen for MDL 74,721. The affinity profile of MDL 74,721 at 5-HT1 receptor subtypes may in part explain its ability to differentiate these two physiological responses. MDL 74,721 demonstrated nanomolar 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). Serotonin-like activity was seen in in vitro functional assays including inhibition of forskolin-stimulated cAMP accumulation in human 5-HT1D receptor-transfected fibroblasts or eliciting vasoconstriction in isolated human pial arteries. The intrinsic activity (relative to 5 - HT[E(Amax)]) and affinity (pD2) for the human cerebrovascular 5-HT receptors were: 5-HT (100%, 7.51 +/- 0.09), sumatriptan (94%, 6.85 +/- 0.1) and MDL 74,721 (66%, 5.70 +/- 0.23). In anaesthetised cats, treatment with MDL 74,721 resulted in a dose-related reduction in the percentage of carotid flow going through the arteriovenous anastomoses to the lungs, with an ED50 of 0.3 mg/kg i.v., the same as sumatriptan. However, in the guinea-pig neurogenic model, MDL 74,721 inhibited plasma protein extravasation with an ED50 of 0.023 microg/kg compared to 2.5 microg/kg for sumatriptan. MDL 74,721 was also effective in this model (in rats) after oral administration. In conclusion, MDL 74,721 demonstrates a preclinical profile consistent with anti-migraine efficacy. Its marked preference for inhibiting neurogenic inflammation makes this compound a useful tool for assessing the relative contribution of this pathophysiological mechanism to the human disease state.
Petty
M A
MA
Marion Merrell, Strasbourg, France. petty21@lsgbw.hcc.com
Elands
J
J
Johnson
M P
MP
Linnik
M D
MD
Hamel
E
E
Moskowitz
M A
MA
Lee
W S
WS
McCarty
D R
DR
Hibert
M
M
Baron
B M
BM
D000818:Animals; D001667:Binding, Competitive; D002415:Cats; D002536:Cerebral Arteries / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D006168:Guinea Pigs; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008881:Migraine Disorders / Q000188:drug therapy / Q000503:physiopathology*; D011903:Raphe Nuclei / Q000098:blood supply / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D018170:Sumatriptan / Q000494:pharmacology*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014276:Trigeminal Nerve / Q000098:blood supply; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
C107347:MDL 74721; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; D013764:Tetrahydronaphthalenes; D014662:Vasoconstrictor Agents; D018170:Sumatriptan; D000242:Cyclic AMP