Pharmacology of 2-amino-1,4-dihydro-4-(2-[4-[4-(2-methoxyphenyl)-1- piperazinyl]butylsulfinyl]phenyl)-6-methyl-5-nitro-3-pyridine carboxylic acid methyl ester (XB513), a novel calcium agonist with alpha-1 adrenergic receptor antagonistic.
2-Amino-1,4-dihydro-4-(2-[-4[4-(2-methoxyphenyl)-1-piperazinyl]- butylsulfinyl]phenyl)-6-methyl-5-nitro-3-pyridine carboxylic acid methyl ester (XB513) was designed to combine the calcium agonistic and alpha-1 adrenergic receptor antagonistic properties in the same molecule. It inhibited the specific binding of [3H] nitrendipine in rat cardiac ventricular membranes with an IC50 of 1.2 microM, which is 20-fold greater than the standard calcium agonist Bay K 8644. It displaced [3H]prazosin in rat brain membranes with an IC50 of 29 nM. XB513 caused concentration-dependent positive inotropic responses in isolated electrically paced guinea pig left atria with an EC50 of 1.2 microM and was 10 times less potent than Bay K 8644. In rabbit aorta, XB513 inhibited the contractile effect of 16 nM norepinephrine with an IC50 of 89 nM. In an acute heart failure dog model produced by an overdose of propranolol, XB513 at 0.3 to 3 mg/kg i.v. dose-dependently reversed the decreased mean arterial pressure, cardiac output and dP/dt as well as the increased left ventricular end diastolic pressure induced by propranolol. In conscious instrumented dogs, XB513 at 0.1 and 0.3 mg/kg i.v. increased dP/dt and heart rate significantly, with a minor effect on mean arterial pressure. In summary, this study demonstrates that XB513 is a novel chemical entity possessing both calcium agonistic and alpha-1 adrenergic receptor blocking properties and thus may represent a new class of agents for the treatment of congestive heart failure.
Wong
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PC
Du Pont Merck Pharmaceutical Company, Wilmington, Delaware.
Aldrich
P E
PE
Chiu
A T
AT
Earl
R A
RA
Hart
S D
SD
Johnson
A L
AL
Ma
P
P
McCall
D E
DE
Price
W A
WA
Smith
R D
RD
D000317:Adrenergic alpha-Antagonists / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002120:Calcium Channel Agonists / Q000737:chemistry / Q000494:pharmacology*; D004095:Dihydropyridines / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D000317:Adrenergic alpha-Antagonists; D002120:Calcium Channel Agonists; D004095:Dihydropyridines; D010879:Piperazines; C081663:XB 513