Pharmacological characterization of novel cyanoguanidines as vascular KATP channel blockers.
KATP blockers derived from cyanoguanidine KATP opener (P1075) chemistry were characterized in isolated rabbit mesenteric artery and evaluated functionally by their ability to antagonize maximal relaxation induced by pinacidil (1 microM) of norepinephrine (5 microM) contraction. PNU-89692, PNU-97025E and PNU-99963 were identified as KATP blockers with IC50 values of 860, 83 and 18 nM, respectively. Studies with selected chiral compounds demonstrated that the (R)-enantiomers were more potent as KATP blockers than the (S)-enantiomers. Further studies demonstrated that PNU-99963 (1) inhibited relaxations by other KATP openers, such as cromakalim (0.5 microM) and minoxidil sulfate (5 microM); (2) was more potent than the other known vascular KATP blockers (glyburide and PNU-37883A); and (3) acted as a KATP blocker in isolated rat aorta as well as dog coronary artery. PNU-99963 actions were selective because PNU-99963 (100 nM) was without any inhibitory effect on relaxations induced by forskolin (0.5 microM), nitroglycerin (1 microM), D600 (25 or 500 nM) or 15 mM K+-induced relaxations of NE contractions in K+-free PSS. The discovery of KATP blockers and openers from the same chemical series is a first for the K+ channel field. The close structural similarity between P1075 (KATP opener) and PNU-99963 (KATP blocker), stereospecificity of action and potency and selectivity all suggest that these molecules may prove to be valuable tools in understanding the structure and function of the KATP channel complex in vascular smooth muscle.
Khan
S A
SA
Cardiovascular Pharmacology and Medicinal Chemistry, Pharmacia and Upjohn, Inc., Kalamazoo, Michigan 49001, USA. Sajida.a.khan@am.pnu.com
Higdon
N R
NR
Hester
J B
JB
Meisheri
K D
KD
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects; D004285:Dogs; D006146:Guanidines / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D026902:Potassium Channel Blockers; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley
D000631:Aminopyridines; D006146:Guanidines; C109642:PNU 99963; D026902:Potassium Channel Blockers; D011725:Pyridines; C073896:N-cyano-N'-(1,1-dimethylpropyl)-N''-(3-pyridinyl)guanidine; D000255:Adenosine Triphosphate