Studies on solution conformations and mechanism of action of amrinone and milrinone

Conference · Wed Mar 05 04:00:00 EST 1986 · Fed. Proc., Fed. Am. Soc. Exp. Biol.; (United States)

OSTI ID:6991704

Beedle, E E; Elzey, T K; Kauffman, R F; Hayes, J S; Robertson, D W

There are two structural differences between the positive inotropes amrinone (A) and milrinone (M): (1) M has a pyridone 2-methyl substituent and; (2) the pyridone 5-amino substituent of A is replaced with a nitrile in M. SAR studies confirmed that the 2-methyl substituent is responsible for the dramatically increased potency of M relative to A (canine i.v. ED/sub 50/'s=37 and 1891 ..mu..g/kg, respectively). Both M and A inhibited canine heart PDEase III (IC/sub 50/'s=12 and 150..mu..M, respectively). Moreover, in a series of M/A congeners, the correlation between in vitro PDEase III IC/sub 50/'s and in vivo inotropic ED/sub 50/'s was highly significant (r = 0.98, p < 0.01). In the crystal-state, the methyl substituent of M induces a marked alteration in its 3-dimensional topology relative to A. They have now completely assigned the /sup 13/C- and /sup 1/H-NMR spectra of A and M and have used the chemical shifts of the pyridone C-4 protons as conformational reporters. These studies revealed that the C-4 protons of methyl containing congeners (M-like) experience a 0.38-0.53 ppm upfield shift relative to the corresponding proton resonance in unmethylated congeners (A-like). These data suggest there are marked, methyl-induced differences in the solution conformations of A and M.

• Research Organization: Lilly Research Labs., Indianapolis, IN
• OSTI ID: 6991704
• Report Number(s): CONF-8604222-
• Conference Information: Journal Name: Fed. Proc., Fed. Am. Soc. Exp. Biol.; (United States) Journal Volume: 45:4
• Country of Publication: United States
• Language: English

Related Subjects

550201* -- Biochemistry-- Tracer Techniques
550600 -- Medicine
59 BASIC BIOLOGICAL SCIENCES
62 RADIOLOGY AND NUCLEAR MEDICINE
BIOCHEMICAL REACTION KINETICS
CARBON 13
CARBON ISOTOPES
CARDIOVASCULAR AGENTS
CHEMICAL SHIFT
DRUGS
EVEN-ODD NUCLEI
ISOTOPES
KINETICS
LIGHT NUCLEI
MAGNETIC RESONANCE
MOLECULAR STRUCTURE
NMR SPECTRA
NUCLEAR MAGNETIC RESONANCE
NUCLEI
REACTION KINETICS
RESONANCE
SPECTRA
STABLE ISOTOPES