Structure-activity relationships of milrinone analogues determined in vitro in a rabbit heart membrane Ca(2+)-ATPase model.
The cardiac activity of a series of analogues of the positive inotropic bipyridines amrinone (5-amino-[3,4'-bipyridin]-6(1H)-one) and milrinone (2-methyl-5-cyano-[3,4'-bipyridin]-6(1H)-one) was evaluated in vitro in a rabbit myocardial membrane Mg(2+)-dependent, Ca(2+)-stimulable adenosine triphosphatase (Ca(2+)-ATPase) model and structure-activity relationships were compared for nine closely related derivatives. In the present studies, a 5-bromo analogue of milrinone stimulated myocardial membrane Ca(2+)-ATPase significantly (10(-7) M; P < 0.001 vs control, with 67% of the activity of milrinone), whereas a 2'-methyl-2H-milrinone derivative was inactive. Although amrinone was inactive in this assay, its 2-methyl analogue was stimulatory. However, analogues lacking a 2-substituent (with or without a 5-cyano group) or with the 3-N position blocked by a methyl group did not stimulate myocardial membrane Ca(2+)-ATPase activity. Structural data for these bipyridines show that those with either a 2- or 2'-methyl substituent have a twist conformation, whereas those without are nearly planar. Activity data reveal that those bipyridines with a nonplanar conformation are more active in the Ca(2+)-ATPase assay. Further study of milrinone analogues with a 2'-methyl substituent shows that even though the effect on the twist angle is equivalent to that of 2-methyl substitution, these analogues are less potent. Data for this series reveal that the prerequisites for Ca(2+)-ATPase stimulation include not only a 2-methyl to maintain a twist conformation but also a free 3-N position and a 5-substituent. This model for optimal activity in the myocardial membrane Ca(2+)-ATPase system differs from those proposed for phosphodiesterase enzyme receptor recognition only in the requirement for a nonplanar molecule. We have previously shown that milrinone, but not amrinone, shares structural homology with thyroxine and was able to stimulate myocardial membrane Ca(2+)-ATPase activity in a manner similar to the thyroid hormone. Additionally, milrinone, but not amrinone, was an effective competitor for thyroxine binding to the serum transport protein transthyretin. Analysis of the milrinone-transthyretin crystal complex confirms the structural homology between milrinone and thyroid hormone which is not shared by amrinone. Modeling studies of the binding interactions of milrinone analogues indicate that the 2-desmethylmilrinone analogue, the most inhibitory analogue, lacks the hydrophobic contacts present in milrinone in its transthyretin-bound complex.(ABSTRACT TRUNCATED AT 400 WORDS)
Cody
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V
Hauptman-Woodward Medical Research Institute, Inc., Buffalo, New York 14203, USA.
Wojtczak
A
A
Davis
F B
FB
Davis
P J
PJ
Blas
S D
SD
D000676:Amrinone / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D000252:Calcium-Transporting ATPases / Q000187:drug effects* / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000737:chemistry* / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006321:Heart / Q000187:drug effects*; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000187:drug effects / Q000201:enzymology; D008566:Membranes / Q000187:drug effects / Q000201:enzymology; D020105:Milrinone; D008968:Molecular Conformation; D015394:Molecular Structure; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism; D011228:Prealbumin / Q000378:metabolism; D011728:Pyridones / Q000737:chemistry* / Q000494:pharmacology*; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology; D013268:Stimulation, Chemical; D013329:Structure-Activity Relationship; D013974:Thyroxine / Q000378:metabolism
D002316:Cardiotonic Agents; D011228:Prealbumin; D011728:Pyridones; D000252:Calcium-Transporting ATPases; D020105:Milrinone; D000676:Amrinone; D013974:Thyroxine