Bisquaternary pyridinium oximes as presynaptic agonists and postsynaptic antagonists of muscarinic receptors.
A study of the effects of bisquaternary pyridinium oximes on calcium-dependent potassium-evoked [3H]acetylcholine release from rat brain slices revealed that at presynaptic autoreceptors these drugs function like muscarinic agonists, as they mimic the effects of acetylcholine in their inhibition of the evoked [3H]-acetylcholine release in an atropine-sensitive and dose-dependent manner. Since the bisquaternary pyridinium oximes are mild muscarinic antagonists at postsynaptic muscarinic receptors, they constitute a category of muscarinic ligands that are characterized by inverse dual activity at pre- and postsynaptic muscarinic receptors. These drugs may have dual function on cholinergic transmission by acting as presynaptic agonists and as postsynaptic antagonists. The most potent inhibitor of the evoked [3H]acetylcholine release was 1,1'-(4-hydroxyiminopyridinium)trimethylene (TMB-4) (I50 = 8 microM) and the weakest were 1-(2-hydroxyiminoethylpyridinium) 1-(3-cyclohexylcarboxypyridinium) dimethylether (HGG-42) and 1-(2-hydroxyiminoethylpyridinium) 1-(3-phenylcarboxypyridinium) dimethylether (HGG-12) (I50 = 150 microM). As postsynaptic antagonists, the latter drugs are more potent (K1 = 1.3-3.3 microM) than TMB-4 (K1 = 50 microM). Combined therapy with two drugs such as TMB-4 and HGG-12 might be effective in blocking severe hyperactivity of the cholinergic system.
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D010091:Oximes / Q000494:pharmacology*; D010095:Oxotremorine / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000494:pharmacology*; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000502:physiology
D010091:Oximes; D011726:Pyridinium Compounds; D011976:Receptors, Muscarinic; D010095:Oxotremorine; D001285:Atropine; D000109:Acetylcholine; D011188:Potassium; D002118:Calcium