A comparison of the cholinergic activity of selected H2-antagonists and sulfoxide metabolites.
Famotidine and selected H2-antagonists were evaluated with respect to toxicity and selected pharmacological activities. When administered intraperitoneally to mice at a dose equivalent to 10 times their respective H2-antagonist ED50 values, no deaths were observed. Similarly, no alteration in brain ACh concentrations or overt pharmacological effects were noted. However, at 400 mg/kg, ranitidine produced 89% lethality, followed by cimetidine (11%) and famotidine. Only cimetidine and famotidine at this dose significantly elevated brain acetylcholine levels. These results do not correlate with the in vitro data, where ORF-17578 and ranitidine were the most potent entities with respect to acetylcholinesterase inhibition (approximately 1-2 X 10(-6) M), followed by nizatidine greater than cimetidine greater than famotidine. The sulfoxide metabolites of ranitidine and cimetidine were approximately one-tenth as potent as their parent compounds with respect to inhibition of acetylcholinesterase. Direct muscarinic stimulation or potentiation of acetylcholine-induced contraction in ileal tissue was not observed for any of the H2-antagonists.
Kosh
J W
JW
Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of South Carolina, Columbia 29208.
Sowell
J W
JW
Chapman
J M
JM
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000378:metabolism; D002927:Cimetidine / Q000378:metabolism / Q000494:pharmacology; D015738:Famotidine / Q000494:pharmacology; D005663:Furans / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D007082:Ileum / Q000187:drug effects; D008297:Male; D051379:Mice; D016567:Nizatidine; D010277:Parasympathomimetics / Q000494:pharmacology*; D011899:Ranitidine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013454:Sulfoxides / Q000378:metabolism / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
D002800:Cholinesterase Inhibitors; D005663:Furans; D006635:Histamine H2 Antagonists; D010277:Parasympathomimetics; D013454:Sulfoxides; D013844:Thiazoles; C061658:2-N,N-dimethylaminomethyl-5-methylfuran; D015738:Famotidine; C048909:ORF 17578; D002927:Cimetidine; D011899:Ranitidine; D000109:Acetylcholine; D016567:Nizatidine