Bipyridine cardiotonics: the three-dimensional structures of amrinone and milrinone.
The cardiotonic drug milrinone (1,6-dihydro-2-methyl-6-oxo-[3,4'-bipyridine]-5-carbonitrile) is superior to its analogue amrinone (5-amino-[3,4'-bipyridin]-6(1H)-one) by virtue of its greater potency and reduced side effect profile. We confirmed initial reports on the potencies of milrinone and amrinone and found that after intravenous administration to phenobarbital anesthetized dogs, the drugs had cumulative inotropic ED50's of 37 and 1891 micrograms/kg, respectively; relative effects on heart rate and blood pressure were comparable. There are two structural differences between amrinone and milrinone: (1) milrinone has a pyridone 2-methyl substituent and (2) the pyridone 5-amino substituent of amrinone is replaced with a nitrile in milrinone. We confirmed structure-activity studies that indicated that the 2-methyl substituent appears to be primarily responsible for the dramatic difference in the potencies of amrinone and milrinone. A plausible explanation for the effect of the methyl substituent is an altered molecular topology resulting from its steric interaction with the 3',5'-hydrogen atoms. Consequently, we probed the three-dimensional structures of these two compounds by X-ray crystallography. The dihedral angle between the planes formed by the two aromatic rings of amrinone was 1.3 degrees. In marked contrast, the corresponding angle for milrinone was 52.2 degrees. Moreover, 1H NMR studies revealed conformational differences in solution. Whereas the 2-methyl substituent undoubtedly produces some electronic and hydrophobic perturbations in the bipyridine cardiotonic series, the most significant effect, from a global viewpoint, is the altered molecular topology.
Robertson
D W
DW
Beedle
E E
EE
Swartzendruber
J K
JK
Jones
N D
ND
Elzey
T K
TK
Kauffman
R F
RF
Wilson
H
H
Hayes
J S
JS
D000631:Aminopyridines / Q000494:pharmacology; D000676:Amrinone; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D003461:Crystallography; D004285:Dogs; D009682:Magnetic Resonance Spectroscopy; D020105:Milrinone; D008958:Models, Molecular; D009200:Myocardial Contraction / Q000187:drug effects; D011728:Pyridones / Q000494:pharmacology; D014961:X-Ray Diffraction
D000631:Aminopyridines; D002316:Cardiotonic Agents; D011728:Pyridones; D020105:Milrinone; D000676:Amrinone