O-Substituted derivatives of pralidoxime: muscarinic properties and protection against soman effects in rats.
O-Substituted aldoximes of the cholinesterase reactivator pralidoxime (O-methyl 1, O-benzyl 2, O-propynyl 3 and O-butynyl 4 derivatives) were synthesized and found to exhibit strong binding affinities for muscarinic receptors in rat brain, heart and submandibulary glands. The aldoximes were noncompetitive antagonists of acetylcholine-induced contraction of the guinea pig ileum. A good correlation was observed between binding affinity and pK(B). Weak anticholinesterase activities were observed for these compounds. When given intracerebroventricularly into conscious rats before soman administration (0.9 LD(50), subcutaneously), the aldoximes, like atropine but not pralidoxime, protected against respiratory depression (3,4) and bradycardia (2). No protection against soman-induced pressor effects was noted. The protective effects of these aldoximes may be the outcome of compensatory mechanisms, of which the cholinergic receptor agonist and antagonist properties of these compounds may be important.
Loke
Weng-Keong
WK
DSO National Laboratories, Singapore
Sim
Meng-Kwoon
MK
Go
Mei-Lin
ML
D000110:Acetylcholinesterase / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D010091:Oximes / Q000378:metabolism / Q000494:pharmacology; D011220:Pralidoxime Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000378:metabolism; D012119:Respiration / Q000187:drug effects; D012999:Soman / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013363:Submandibular Gland / Q000378:metabolism
D018679:Cholinergic Agonists; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D018727:Muscarinic Antagonists; D010091:Oximes; D011220:Pralidoxime Compounds; D011976:Receptors, Muscarinic; D001285:Atropine; D002217:Carbachol; D012999:Soman; D000110:Acetylcholinesterase; C023728:acetaldehyde oxime; C028797:pralidoxime