Pharmacological profile of a new 5-hydroxytryptamine2 receptor antagonist, DV-7028.
The pharmacological profile of DV-7028, a pyrido triazine derivative, showed that it is a potent and selective 5-hydroxytryptamine (5-HT)2 receptor antagonist. DV-7028 bound to 5-HT2 receptors in rat brain membranes with a Ki value of 22 nM and caused shifts to the right of the concentration-contraction curves to 5-HT in rat thoracic aorta and canine femoral arteries, which are attributed to activation of 5-HT2 receptors. The compound was highly active by oral administration (0.1-10 mg/kg) based on blockade of the 5-HT-induced pressor responses in pithed rats. In contrast, DV-7028 had no affinity for 5-HT1A, 5-HT1B and 5-HT1D receptors. The affinity of the compound was 14-26 times greater for the 5-HT2 receptors when compared to 5-HT1C, adrenergic alpha 1, dopamine D2 and histamine H1 receptors. In human platelets, DV-7028 attenuated the aggregation induced by collagen and inhibited the amplifying effect of 5-HT with collagen on platelet aggregation. Furthermore, a 10-day toxicity study revealed that DV-7028 was a safe compound which did not produce lethality at repeated oral doses of 800 mg/kg/day in rats. These results indicate that DV-7028 is a selective and potent 5-HT2 receptor antagonist which is orally active and safe.
Shibano
T
T
Exploratory Research Laboratories II, Tokyo R & D Center, Daiichi Pharmaceutical Co., Ltd., Japan.
Tanaka
T
T
Morishima
Y
Y
Yasuoka
M
M
Watanabe
K
K
Fujii
F
F
D000818:Animals; D001011:Aorta; D003655:Decerebrate State; D004285:Dogs; D005263:Femoral Artery; D005748:Gastric Fundus; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000032:analysis / Q000187:drug effects; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014227:Triazines / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity
D010880:Piperidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D014227:Triazines; C073727:DV 7028; D007650:Ketanserin