BMS-181885, a 5-HT1B/1D receptor ligand, in experimental models predictive of antimigraine activity and coronary side-effect potential.
Many acutely acting antimigraine drugs have the ability to constrict porcine arteriovenous anastomoses as well as the human isolated 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 investigated the effects of BMS-181885 (3-[3-[4-(5-methoxy-4-pyrimidyl)-1-piperazinyl]propyl]-5-(1,2-dioxo-4-me thyl-3-cyclobuten-3-yl)amino-1H-indole), a 5-HT1B/1D receptor ligand. In anaesthetised pigs, BMS-181885 (10, 30, 100 and 300 microg kg(-1)) decreased the total carotid blood flow and conduction, exclusively at the expense of the arteriovenous anastomotic fraction as the capillary fraction did in fact increase. The highest dose (300 microg kg(-1)) produced a reduction of 52+/-6% from the baseline arteriovenous anastomotic flow. When carotid haemodynamic changes after a single 100 microg kg(-1)dose of BMS-181885 or sumatriptan were studied at different time-points, BMS-188185 had a longer duration of action. Both BMS-181885 (pD2:7.9+/-0.1; Emax:9+/-3% of the contraction to 100 mM K+) and sumatriptan (pD2:6.3+/-0.1; Emax:28+/-8% of the contraction to 100 mM K+) contracted the human isolated coronary artery. The above results suggest that (i) the longer-lasting vasoconstrictor action of BMS-181885 on porcine carotid arteriovenous anastomoses may be related to its reported slow dissociation from 5-HT1B/1D receptor, and (ii) BMS-181885 should be able to abort migraine headaches in patients. It will be interesting to find out whether these properties are clinically important so that the drug exhibits less headache recurrence and coronary side-effects than sumatriptan.
Department of Pharmacology, Dutch Migraine Research Group and Cardiovascular Research Institute COEUR, Faculty of Medicine and Health Sciences, Erasmus University Rotterdam, Netherlands. saxena@farma.fgg.eur.nl
P R
PR
Saxena
P
P
De Vries
J P
JP
Heiligers
W A
WA
Bax
A
A
Maassen VanDenBrink
F D
FD
Yocca
D000818:Animals; D001163:Arteriovenous Anastomosis / Q000187:drug effects / Q000502:physiology; D002339:Carotid Arteries / Q000187:drug effects / Q000502:physiology; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology* / Q000633:toxicity; D007601:Jugular Veins / Q000187:drug effects / Q000502:physiology; D008881:Migraine Disorders / Q000188:drug therapy* / Q000503:physiopathology; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010100:Oxygen / Q000097:blood; D010879:Piperazines / Q000494:pharmacology* / Q000633:toxicity; D011188:Potassium / Q000494:pharmacology; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology* / Q000633:toxicity; D013373:Substance P / Q000494:pharmacology; D018170:Sumatriptan / Q000494:pharmacology / Q000633:toxicity; D013552:Swine; D014662:Vasoconstrictor Agents / Q000494:pharmacology* / Q000633:toxicity
C111853:BMS 181885; C470302:HTR1B protein, human; D007211:Indoles; D010879:Piperazines; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D014662:Vasoconstrictor Agents; D013373:Substance P; D018170:Sumatriptan; D011188:Potassium; D010100:Oxygen