Reversible and irreversible inhibition of rat brain muscarinic receptors is related to different substitutions on bisquaternary pyridinium oximes |
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Authors: | Kloog Y Galron R Balderman D Sokolovsky M |
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Institution: | (1) Department of Biochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978 Tel-Aviv, Israel;(2) Israel Institute for Biological Research, Ness-Ziona, Israel |
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Abstract: | The role of the functional substituents on the pyridinium ring of bisquaternary pyridinium compounds, mostly oximes, in exerting reversible and irreversible inhibition of binding of 3H]-N-methyl-4-piperidyl benzilate (3H]-4NMPB) to rat brain stem muscarinic receptors was studied. The drugs tested, i.e. HGG-42, HGG-12, HGG-52, HI-6, obidoxim, SAD-128 and TMB-4, could reversibly inhibit binding of 3H]-4NMPB, with the highest potency (KI=1.7–6 M) exhibited by analogs possessing hydrophobic substituents at position 3 or 4 of the pyridinium ring. Bisquaternary drugs possessing an oxime moiety at position 2, but not at position 4 of the pyridinium ring, could also induce about 30% reduction of maximal binding capacity (Bmax) (loss of muscarinic receptors) in addition to their reversible effect. Thus the structural correlates of the reversible and the irreversible effects of these drugs are different. |
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Keywords: | Muscarinic receptor bisquaternary pyridinium oximes Receptor inactivation Brain stem |
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