Cardiovascular pharmacological characterization of novel 2,3-dimethyl-2-butylamine derivatives in rats.
The electrophysiological properties and pharmacological effects of newly synthesized 2,3-dimethyl-2-butylamine derivatives on the rat cardiovascular system were evaluated both in vitro and in vivo. In conventional whole-cell recordings, 2,3-dimethyl-2-butylamine derivatives with ethyl, isopropyl, allyl, butyl, 1-methyl-propyl or cyclopropylmethyl substituents on the amine side chain had potent effects on the outward potassium currents in isolated rat tail arterial smooth muscle cell membranes. In contrast, the compounds with hydrogen, methyl, propyl or benzyl substituents displayed very low activities, which were not statistically significant. The effects of compounds with pyridine ring substituents were also investigated and their order of potency was (14)>(12)>(13). In addition, the opening activities of these compounds (5), (6), (8) could be prevented by glibenclamide, a highly specific blocker of ATP-sensitive potassium channels. The influences of the compounds on cardiovascular hemodynamics parameters, including mean blood pressure (MBP), heat rate (HR), myocardial contractility and diastolic force, were examined in normotensive anesthetized rats. The derivatives with branched 2-4 carbon alkyl substituents induced long-duration hypotensive effects with modest inhibition of cardiac function. The hypotensive effects of the compound (5) could also be inhibited by glibenclamide. Collectively, these results indicate that 2,3-dimethyl-2-butylamine derivatives, which differ chemically from previously described potassium channel openers, have potassium channel opening activity, hypotensive and cardiac-modulating properties that depend on their amino group substituents.
Chen
Yu-Ping
YP
Department of Cardiovascular Pharmacology, Beijing Institute of Pharmacology and Toxicology, 100850, PR China.
Qiu
Cai-Rong
CR
Wang
Hai
H
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001158:Arteries / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D002082:Butylamines / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005905:Glyburide / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013623:Tail / Q000098:blood supply; D013997:Time Factors
D000959:Antihypertensive Agents; D002082:Butylamines; D015221:Potassium Channels; D011188:Potassium; D005905:Glyburide