Pharmacological activities of acetal derivatives of hemicholinium no. 3.
Acetal derivatives of hemicholinium no. 3 (HC-3) were synthesized and their chemical structures were confirmed by spectrophotometric evidence and elemental analysis. The acetals elicited a biphasic pattern of neuromuscular inhibition in the cat: (a) an immediate inhibition (early phase block) was judged to be curare-like as responses to acetylcholine (close i.a.) were abolished by acetal administration and reversal of inhibition was effected by neostigmine (25 micrograms/kg); (b) a slow, progressive inhibition of transmission (late phase block) was considered HC-3-like as it occurred only during high frequency stimulation and was antagonized by small doses of choline (1--3 mg/kg). In comparison to HC-3, significanlty greater curare-like activity was noted following acetal administration in vivo and in vitro. Mouse toxicity and cat nerve--muscle studies revealed the acetals to be HC-3-like but 1/2 to 1/3 as active as the parent compound. Cholinesterase inhibition by HC-3 and the acetals was low (I50 greater than 0.1 mM) and did not account for differences in activities. Acetal-elicited hypotension in the cat was attributed to postsynaptic ganglionic blockade and histamine release. Studies employing the 14C-(N-methyl) acetals furnished no evidence of the bioactivation (O-dealkylation) of the acetals to HC-3 in the cat in vivo or in cat liver in vitro. Chromatographic analysis afforded no evidence of molecular modifications of 14C-HC-3 or of the 14C-acetals in these systems.
D000080:Acetals / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002415:Cats; D055598:Chemical Phenomena; D002621:Chemistry; D002800:Cholinesterase Inhibitors; D005260:Female; D006426:Hemicholinium 3 / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D066298:In Vitro Techniques; D007928:Lethal Dose 50; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D009469:Neuromuscular Junction / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship; D009435:Synaptic Transmission / Q000187:drug effects
D000080:Acetals; D002800:Cholinesterase Inhibitors; D006426:Hemicholinium 3