Acetylsecohemicholinium: chemical and pharmacological evaluation of an open-ring hemicholinium.
Acetylsecohemicholinium No. 3 (AcHC-3), the acetate of the open ring (seco form of hemicholinium No. 3, HC-3) hydrolyzes in vitro to the hemiacetal HC-3 at pH values above 9, a temperature-dependent conversion illustrated by ultraviolet spectral shifts from 305 to 257 mmu, and to a limited extent by certain esterases as measured by manometric analysis. An LD50 of 125 mug/kg for a neutral solution of AcHC-3 was decreased to 78.3 mug/kg (the LD50 of HC-3) upon being made basic. Prolonged treatment of mice with LD10-20 doses of AcHC-3 was associated with decreased fatty acid oxidation in the liver and resulted in infiltration of fat into hepatic cells, a reaction preventable by treatment with small doses of choline (10 mg/kg). AcHC-3 causes neuromuscular and autonomic ganglionic blockade, cholinesterase inhibition, and in vitro inhibition of acetylcholine (ACh) synthesis. These actions, although HC-3-like, appear to be due to AcHC-3 rather than HC-3 since neither cholinesterase inhibition nor hepatic ligation altered the neuromuscular blocking actions of AcHC-3. In addition to its HC-3-like properties, AcHC-3 consistently produced a transient increase in twitch height of gastrocnemius muscle before blockade and was dose-responsive in depressing blood pressure and in eliciting contractions of the isolated guinea pig ileum. AcHC-3 is both a cholinomimetic (depresses arterial blood pressure, decreases heart rate and increases ileal contractions) and a competitor of acetylcholine. That is, in most preparations tested, AcHC-3 at lower concentrations has as much intrinsic activity as ACh and at somewhat higher concentrations competitively blocks the responses to ACh. These cholinomimetic actions may be due to the presence of two ACh moieties on the AcHC-3 molecule which attach to cholinergic receptor sites. Also noted was an action of AcHC-3 that seems to be peculiar to the secohemicholiniums, namely, the potentiation of catechloamines.
D000109:Acetylcholine / Q000096:biosynthesis; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D002415:Cats; D055598:Chemical Phenomena; D002621:Chemistry; D002800:Cholinesterase Inhibitors; D005227:Fatty Acids / Q000378:metabolism; D005725:Ganglia, Autonomic / Q000187:drug effects; D005730:Ganglionic Blockers; D006339:Heart Rate / Q000187:drug effects; D006426:Hemicholinium 3 / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D008099:Liver / Q000378:metabolism; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D010084:Oxidation-Reduction; D013569:Synapses / Q000187:drug effects
D002800:Cholinesterase Inhibitors; D005227:Fatty Acids; D005730:Ganglionic Blockers; D006426:Hemicholinium 3; D000109:Acetylcholine