Cardiovascular effects of KM-13, a new, orally effective, cardiotonic sympathomimetic amine

Robert William Caldwell, Clinton B. Nash, Maciej Smulkowski, Ronald R. Tuttle

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Dobutamine's chemical structure was modified to make it orally effective, while its pharmacological profile was preserved. Testing on anesthetized dogs showed that replacement of the para hydroxyl group with carboxyamide at the phenyl end of the molecule increased inotropic potency threefold, but it introduced pressor activity that spoiled the inotropic selective profile of dobutamine. However, shifting carboxyamide to the meta position avoided pressor activity and further enhanced inotropic potency to nine times that of dobutamine. When administered orally to conscious dogs, this compound, KM-13 (5 mg/kg), produced a sustained increase in left ventricular dP/dt with only immediate changes in heart rate; 10 mg/kg dobutamine was without cardiovascular effects. The (-) isomer of KM-13 contained twice the inotropic activity of the (+) isomer; in contrast, the (-) isomer had no effect on diastolic blood pressure, while the (+) isomer lowered blood pressure. The inotropic and chronotropic effects of dobutamine and KM-13 are both largely due to β-adrenergic stimulation as shown by propranolol blockade. In contrast to dobutamine, KM-13 is an agent that is active by either oral or buccal administration and has greater inotropic potency.

Original languageEnglish (US)
Pages (from-to)375-384
Number of pages10
JournalJournal of Cardiovascular Pharmacology
Volume9
Issue number3
DOIs
StatePublished - Jan 1 1987
Externally publishedYes

Fingerprint

Cardiotonic Agents
Sympathomimetics
Dobutamine
Blood Pressure
Buccal Administration
Dogs
Propranolol
Hydroxyl Radical
Adrenergic Agents
Oral Administration
4-(2-((3-(3-benzenecarboxamide)-1-methylpropyl)amino)ethyl)-1,2-benzenediol
Heart Rate
Pharmacology

Keywords

  • Cardiovascular
  • Dobutamine
  • Dog
  • KM-13
  • Oral
  • Sympathomimetic amine

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

Cite this

Cardiovascular effects of KM-13, a new, orally effective, cardiotonic sympathomimetic amine. / Caldwell, Robert William; Nash, Clinton B.; Smulkowski, Maciej; Tuttle, Ronald R.

In: Journal of Cardiovascular Pharmacology, Vol. 9, No. 3, 01.01.1987, p. 375-384.

Research output: Contribution to journalArticle

Caldwell, Robert William ; Nash, Clinton B. ; Smulkowski, Maciej ; Tuttle, Ronald R. / Cardiovascular effects of KM-13, a new, orally effective, cardiotonic sympathomimetic amine. In: Journal of Cardiovascular Pharmacology. 1987 ; Vol. 9, No. 3. pp. 375-384.
@article{08d5d7d4641c473891ca0c7e069f7046,
title = "Cardiovascular effects of KM-13, a new, orally effective, cardiotonic sympathomimetic amine",
abstract = "Dobutamine's chemical structure was modified to make it orally effective, while its pharmacological profile was preserved. Testing on anesthetized dogs showed that replacement of the para hydroxyl group with carboxyamide at the phenyl end of the molecule increased inotropic potency threefold, but it introduced pressor activity that spoiled the inotropic selective profile of dobutamine. However, shifting carboxyamide to the meta position avoided pressor activity and further enhanced inotropic potency to nine times that of dobutamine. When administered orally to conscious dogs, this compound, KM-13 (5 mg/kg), produced a sustained increase in left ventricular dP/dt with only immediate changes in heart rate; 10 mg/kg dobutamine was without cardiovascular effects. The (-) isomer of KM-13 contained twice the inotropic activity of the (+) isomer; in contrast, the (-) isomer had no effect on diastolic blood pressure, while the (+) isomer lowered blood pressure. The inotropic and chronotropic effects of dobutamine and KM-13 are both largely due to β-adrenergic stimulation as shown by propranolol blockade. In contrast to dobutamine, KM-13 is an agent that is active by either oral or buccal administration and has greater inotropic potency.",
keywords = "Cardiovascular, Dobutamine, Dog, KM-13, Oral, Sympathomimetic amine",
author = "Caldwell, {Robert William} and Nash, {Clinton B.} and Maciej Smulkowski and Tuttle, {Ronald R.}",
year = "1987",
month = "1",
day = "1",
doi = "10.1097/00005344-198703000-00015",
language = "English (US)",
volume = "9",
pages = "375--384",
journal = "Journal of Cardiovascular Pharmacology",
issn = "0160-2446",
publisher = "Lippincott Williams and Wilkins",
number = "3",

}

TY - JOUR

T1 - Cardiovascular effects of KM-13, a new, orally effective, cardiotonic sympathomimetic amine

AU - Caldwell, Robert William

AU - Nash, Clinton B.

AU - Smulkowski, Maciej

AU - Tuttle, Ronald R.

PY - 1987/1/1

Y1 - 1987/1/1

N2 - Dobutamine's chemical structure was modified to make it orally effective, while its pharmacological profile was preserved. Testing on anesthetized dogs showed that replacement of the para hydroxyl group with carboxyamide at the phenyl end of the molecule increased inotropic potency threefold, but it introduced pressor activity that spoiled the inotropic selective profile of dobutamine. However, shifting carboxyamide to the meta position avoided pressor activity and further enhanced inotropic potency to nine times that of dobutamine. When administered orally to conscious dogs, this compound, KM-13 (5 mg/kg), produced a sustained increase in left ventricular dP/dt with only immediate changes in heart rate; 10 mg/kg dobutamine was without cardiovascular effects. The (-) isomer of KM-13 contained twice the inotropic activity of the (+) isomer; in contrast, the (-) isomer had no effect on diastolic blood pressure, while the (+) isomer lowered blood pressure. The inotropic and chronotropic effects of dobutamine and KM-13 are both largely due to β-adrenergic stimulation as shown by propranolol blockade. In contrast to dobutamine, KM-13 is an agent that is active by either oral or buccal administration and has greater inotropic potency.

AB - Dobutamine's chemical structure was modified to make it orally effective, while its pharmacological profile was preserved. Testing on anesthetized dogs showed that replacement of the para hydroxyl group with carboxyamide at the phenyl end of the molecule increased inotropic potency threefold, but it introduced pressor activity that spoiled the inotropic selective profile of dobutamine. However, shifting carboxyamide to the meta position avoided pressor activity and further enhanced inotropic potency to nine times that of dobutamine. When administered orally to conscious dogs, this compound, KM-13 (5 mg/kg), produced a sustained increase in left ventricular dP/dt with only immediate changes in heart rate; 10 mg/kg dobutamine was without cardiovascular effects. The (-) isomer of KM-13 contained twice the inotropic activity of the (+) isomer; in contrast, the (-) isomer had no effect on diastolic blood pressure, while the (+) isomer lowered blood pressure. The inotropic and chronotropic effects of dobutamine and KM-13 are both largely due to β-adrenergic stimulation as shown by propranolol blockade. In contrast to dobutamine, KM-13 is an agent that is active by either oral or buccal administration and has greater inotropic potency.

KW - Cardiovascular

KW - Dobutamine

KW - Dog

KW - KM-13

KW - Oral

KW - Sympathomimetic amine

UR - http://www.scopus.com/inward/record.url?scp=0023130764&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0023130764&partnerID=8YFLogxK

U2 - 10.1097/00005344-198703000-00015

DO - 10.1097/00005344-198703000-00015

M3 - Article

C2 - 2437405

AN - SCOPUS:0023130764

VL - 9

SP - 375

EP - 384

JO - Journal of Cardiovascular Pharmacology

JF - Journal of Cardiovascular Pharmacology

SN - 0160-2446

IS - 3

ER -