Showing papers by "Frank D. Yocca published in 1997"

Effects of avitriptan, a new 5-HT 1B/1D receptor agonist, in experimental models predictive of antimigraine activity and coronary side-effect potential

Abstract: Several acutely acting antimigraine drugs, includ- ing ergotamine and sumatriptan, have the ability to constrict porcine arteriovenous anastomoses as well as the human iso- lated coronary artery. These two experimental models seem to serve as indicators, respectively, for the therapeutic and coronary side-effect potential of the compounds. Using these two models, we have now investigated the effects of avitriptan (BMS-180048; 3-(3-(4-(5-methoxy-4-pyrimidi- nyl)-1-piperazinyl)propyl)-N-methyl-1H-indole-5-methane- sulfonamide monofumarate), a new 5-HT1B/1D receptor ago- nist. In anaesthetized pigs, avitriptan (10, 30, 100 and 300 lg·kg -1 ) decreased the total carotid blood flow by ex- clusively decreasing arteriovenous anastomotic blood flow; capillary blood flow was increased. The mean ± SEM i.v. dose of avitriptan eliciting a 50% decrease (ED50) in the por- cine carotid arteriovenous anastomotic blood flow was cal- culated to be 76 ± 23lg·kg -1 (132 ± 40 nmol·kg -1 ) and the highest dose (300 lg·kg -1 ) produced a 72 ± 4% reduc- tion. In recent comparative experiments (DeVries et al. 1996), the mean ± SEM ED 50 (i.v.) of sumatriptan in de- creasing carotid arteriovenous anastomotic blood flow was 63 ± 17lg·kg -1 (158 ± 43 nmol·kg -1 ), with a reduction of 76 ± 4% by 300lg·kg -1 , i.v. Both avitriptan (pD2: 7.39 ± 0.09; Emax: 13.0 ± 4.5% of the contraction to 100 mM K + ) and sumatriptan (pD2: 6.33 ± 0.09; Emax: 15.5 ± 2.3% of the contraction to 100 mM K + ) contracted the human isolated coronary artery. The above results sug- gest that avitriptan should be able to abort migraine head- aches in patients, but may exhibit sumatriptan-like effects on coronary arteries. Initial clinical studies have demon- strated the therapeutic action of the drug in acute migraine.

Second generation antimigraine 5-Ht1B/D agonists : Structure activity relationship and preclinical pharmacological distinctions

Abstract: The discovery and development of the 5-HT 1b/D agonist sumatriptan for alleviating migraine pain has been an important advance in the field of modern headache treatment and research. This important therapeutic advance is not without it's shortcomings. When administred orally, its poorly absorbed with clinically relevant headache relief occuring at least two hours afer drug administration. Due to its agonist action is peripherovascular 5-HT 1D-like receptors, it is contraindicated in patients with coronary artery disease. Furthermore, headache recurs within a 24 hour period in 40% of patients treated. Given the large unmet medical need; market size and sumitriptan's shortcomings, a number of second-generation agents have been developed which are structurally and pharmacologically similar to simatriptan, but have improved oral pharmacokinetic profiles. These include zolmitriptan, naratriptan, rizatriptan; avitriptan, alnitripan,eletriptan, and BMS-181885, all of which have been shown to be clinically effective. In this review, the SAR of the second generation triptans at the 5-HT 1B and 5-HT 1D receptors as well as distinct pharmacological actions in novel animal model are discussed