End-plate ion channel block produced by lincosamide antibiotics and their chemical analogs

C Prior, J F Fiekers, F Henderson, J Dempster, I G Marshall, R L Parsons

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Five lincosamide compounds were studied for their effects on end-plate currents (epcs), miniature end-plate currents and acetylcholine-induced current fluctuations in the garter snake costocutaneous nerve-muscle preparation. At high concentrations, lincomycin and clindamycin reduced epc amplitude, but analysis of driving functions showed that only with clindamycin was this due solely to changes in epc quantal content. The effect of lincomycin on epc amplitude was exaggerated by rapid channel block during the rising phase of the epc. Clindamycin produced currents with a single exponential decay and single Lorentzian noise spectra. All the other compounds produced currents which decayed as the sum of two exponential components. For lincomycin and epilincomycin, noise spectra consisted of two Lorentzian components. For epiclindamycin and deoxylincomycin, although epcs and miniature end-plate currents decayed with two components, it was not possible to separate two components in the noise spectra. A kinetic analysis of ion channel blocking actions showed only small differences between the two pairs of stereoisomers studied. End-plate ion channel blocking and unblocking rate constants did not vary greatly among the compounds but the end-plate ion channel unblocking rate constant values for the two lincomycin stereoisomers were larger than those for the two clindamycin stereoisomers. Deoxylincomycin exhibited properties similar to those of the clindamycins. It was concluded that lipid solubility, not stereochemical conformation, plays the greater role in determining the ion channel blocking properties within the series, particularly that of the rate of dissociation of the compound from end-plate ion channels.
LanguageEnglish
Pages1170-1176
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume255
Issue number3
DOIs
Publication statusPublished - Dec 1990

Fingerprint

Lincosamides
Lincomycin
Clindamycin
Ion Channels
Stereoisomerism
Anti-Bacterial Agents
Noise
Colubridae
Neuromuscular Junction
Solubility
Acetylcholine
Lipids

Keywords

  • animals
  • anti-bacterial agents
  • clindamycin
  • ion channels
  • kinetics
  • lincomycin
  • lincosamides
  • macrolides
  • membrane potentials
  • motor endplate
  • neuromuscular junction
  • snakes
  • structure-activity relationship

Cite this

Prior, C ; Fiekers, J F ; Henderson, F ; Dempster, J ; Marshall, I G ; Parsons, R L. / End-plate ion channel block produced by lincosamide antibiotics and their chemical analogs. In: Journal of Pharmacology and Experimental Therapeutics. 1990 ; Vol. 255, No. 3. pp. 1170-1176.
@article{2dc152addc4e4eeab8d5a02dd9479edb,
title = "End-plate ion channel block produced by lincosamide antibiotics and their chemical analogs",
abstract = "Five lincosamide compounds were studied for their effects on end-plate currents (epcs), miniature end-plate currents and acetylcholine-induced current fluctuations in the garter snake costocutaneous nerve-muscle preparation. At high concentrations, lincomycin and clindamycin reduced epc amplitude, but analysis of driving functions showed that only with clindamycin was this due solely to changes in epc quantal content. The effect of lincomycin on epc amplitude was exaggerated by rapid channel block during the rising phase of the epc. Clindamycin produced currents with a single exponential decay and single Lorentzian noise spectra. All the other compounds produced currents which decayed as the sum of two exponential components. For lincomycin and epilincomycin, noise spectra consisted of two Lorentzian components. For epiclindamycin and deoxylincomycin, although epcs and miniature end-plate currents decayed with two components, it was not possible to separate two components in the noise spectra. A kinetic analysis of ion channel blocking actions showed only small differences between the two pairs of stereoisomers studied. End-plate ion channel blocking and unblocking rate constants did not vary greatly among the compounds but the end-plate ion channel unblocking rate constant values for the two lincomycin stereoisomers were larger than those for the two clindamycin stereoisomers. Deoxylincomycin exhibited properties similar to those of the clindamycins. It was concluded that lipid solubility, not stereochemical conformation, plays the greater role in determining the ion channel blocking properties within the series, particularly that of the rate of dissociation of the compound from end-plate ion channels.",
keywords = "animals, anti-bacterial agents, clindamycin, ion channels, kinetics, lincomycin, lincosamides, macrolides, membrane potentials, motor endplate, neuromuscular junction, snakes, structure-activity relationship",
author = "C Prior and Fiekers, {J F} and F Henderson and J Dempster and Marshall, {I G} and Parsons, {R L}",
year = "1990",
month = "12",
doi = "10.1111/j.1469-7793.1998.451bh.x",
language = "English",
volume = "255",
pages = "1170--1176",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
number = "3",

}

End-plate ion channel block produced by lincosamide antibiotics and their chemical analogs. / Prior, C; Fiekers, J F; Henderson, F; Dempster, J; Marshall, I G; Parsons, R L.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 255, No. 3, 12.1990, p. 1170-1176.

Research output: Contribution to journalArticle

TY - JOUR

T1 - End-plate ion channel block produced by lincosamide antibiotics and their chemical analogs

AU - Prior, C

AU - Fiekers, J F

AU - Henderson, F

AU - Dempster, J

AU - Marshall, I G

AU - Parsons, R L

PY - 1990/12

Y1 - 1990/12

N2 - Five lincosamide compounds were studied for their effects on end-plate currents (epcs), miniature end-plate currents and acetylcholine-induced current fluctuations in the garter snake costocutaneous nerve-muscle preparation. At high concentrations, lincomycin and clindamycin reduced epc amplitude, but analysis of driving functions showed that only with clindamycin was this due solely to changes in epc quantal content. The effect of lincomycin on epc amplitude was exaggerated by rapid channel block during the rising phase of the epc. Clindamycin produced currents with a single exponential decay and single Lorentzian noise spectra. All the other compounds produced currents which decayed as the sum of two exponential components. For lincomycin and epilincomycin, noise spectra consisted of two Lorentzian components. For epiclindamycin and deoxylincomycin, although epcs and miniature end-plate currents decayed with two components, it was not possible to separate two components in the noise spectra. A kinetic analysis of ion channel blocking actions showed only small differences between the two pairs of stereoisomers studied. End-plate ion channel blocking and unblocking rate constants did not vary greatly among the compounds but the end-plate ion channel unblocking rate constant values for the two lincomycin stereoisomers were larger than those for the two clindamycin stereoisomers. Deoxylincomycin exhibited properties similar to those of the clindamycins. It was concluded that lipid solubility, not stereochemical conformation, plays the greater role in determining the ion channel blocking properties within the series, particularly that of the rate of dissociation of the compound from end-plate ion channels.

AB - Five lincosamide compounds were studied for their effects on end-plate currents (epcs), miniature end-plate currents and acetylcholine-induced current fluctuations in the garter snake costocutaneous nerve-muscle preparation. At high concentrations, lincomycin and clindamycin reduced epc amplitude, but analysis of driving functions showed that only with clindamycin was this due solely to changes in epc quantal content. The effect of lincomycin on epc amplitude was exaggerated by rapid channel block during the rising phase of the epc. Clindamycin produced currents with a single exponential decay and single Lorentzian noise spectra. All the other compounds produced currents which decayed as the sum of two exponential components. For lincomycin and epilincomycin, noise spectra consisted of two Lorentzian components. For epiclindamycin and deoxylincomycin, although epcs and miniature end-plate currents decayed with two components, it was not possible to separate two components in the noise spectra. A kinetic analysis of ion channel blocking actions showed only small differences between the two pairs of stereoisomers studied. End-plate ion channel blocking and unblocking rate constants did not vary greatly among the compounds but the end-plate ion channel unblocking rate constant values for the two lincomycin stereoisomers were larger than those for the two clindamycin stereoisomers. Deoxylincomycin exhibited properties similar to those of the clindamycins. It was concluded that lipid solubility, not stereochemical conformation, plays the greater role in determining the ion channel blocking properties within the series, particularly that of the rate of dissociation of the compound from end-plate ion channels.

KW - animals

KW - anti-bacterial agents

KW - clindamycin

KW - ion channels

KW - kinetics

KW - lincomycin

KW - lincosamides

KW - macrolides

KW - membrane potentials

KW - motor endplate

KW - neuromuscular junction

KW - snakes

KW - structure-activity relationship

U2 - 10.1111/j.1469-7793.1998.451bh.x

DO - 10.1111/j.1469-7793.1998.451bh.x

M3 - Article

VL - 255

SP - 1170

EP - 1176

JO - Journal of Pharmacology and Experimental Therapeutics

T2 - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 3

ER -