A novel orally active dopamine prodrug TA-870. II. Evidence that TA-870 is a dopamine prodrug.
The mechanism of action of a new orally active dopamine (DA) prodrug, TA-870 (N-(N-acetyl-L-methionyl)-O,O-bis(ethoxycarbonyl)(DA) was studied. When TA-870 (1 mg/kg) was injected in anesthetized dogs, renal vascular resistance was decreased and renal blood flow was increased. The renal vasodilatory effect of TA-870 correlated with the plasma level of DA but not with the level of de-ethoxycarbonyl metabolite of TA-870 (i.e., N-(N-acetyl-L-methionyl)DA; DEC-TA-870). The renal vasodilatory effect of TA-870 was inhibited strongly by haloperidol and slightly by propranolol. Pretreatment with phenoxybenzamine enhanced the renal vasodilatory effect of TA-870. In the isolated rabbit splenic artery, TA-870 and DEC-TA-870 showed no effects, whereas dopamine showed a contracting effect, which was inhibited by phentolamine. In the propranolol- and phentolamine-treated splenic artery, TA-870 and DEC-TA-870 caused weak relaxant effects on PGF2 alpha-induced contraction. These effects were not antagonized by metoclopramide. On the other hand, DA showed a strong relaxant effect, which was competitively inhibited by metoclopramide. In addition, TA-870 and DEC-TA-870 further relaxed the artery that had been maximally relaxed by DA. We concluded that TA-870 and DEC-TA-870 exert weak vasodilatory effects that are different from that of DA in vitro, and that TA-870 exerts its vasodilatory effect after its conversion to free DA in vivo.
Nishiyama
S
S
Biological Research Laboratory, Toda, Japan.
Yamaguchi
I
I
Akimoto
Y
Y
Yoshikawa
M
M
Nakajima
H
H
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004298:Dopamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006220:Haloperidol / Q000494:pharmacology; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007441:Intubation, Gastrointestinal; D008297:Male; D010643:Phenoxybenzamine / Q000494:pharmacology; D011355:Prodrugs; D011433:Propranolol / Q000494:pharmacology; D011817:Rabbits; D012079:Renal Circulation / Q000187:drug effects; D013157:Splenic Artery / Q000187:drug effects
D011355:Prodrugs; D010643:Phenoxybenzamine; D011433:Propranolol; D006220:Haloperidol; C052143:docarpamine; D004298:Dopamine