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

Prior, C and Fiekers, J F and Henderson, F and Dempster, J and Marshall, I G and Parsons, R L (1990) End-plate ion channel block produced by lincosamide antibiotics and their chemical analogs. Journal of Pharmacology and Experimental Therapeutics, 255 (3). pp. 1170-1176. ISSN 0022-3565

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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.