Stereoisomers of quaternary and tertiary 4-methyl piperidine analogs of hemicholinium-3.
Previous studies have shown that quaternary and tertiary 4-methyl piperidine derivatives of hemicholinium-3 (A-5 and A-4, respectively) are potent inhibitors of choline uptake. The d-, l-, and mesostereoisomers of A-5 and A-4 were separated and the potency and reversibility were compared. Isomeric forms of each compound were found to be approximately equipotent inhibitors in the following preparations: inhibition of rabbit neuromuscular transmission using the sciatic nerve-gastrocnemius muscle preparation, reductions in acetylcholine content in rat caudate tissue slices and inhibition of choline uptake in neuroblastoma cells, line NB41A3. Because these results show no difference in potency or reversibility for the stereoisomers of A-5 or A-4, these studies indicate that hydroxyl substitutions in these agents do not play a role in their biologic activity. Perhaps only 2-point attachment is required for inhibition of choline transport by hemicholinium-like compounds.
Sheff
K Y
KY
Department of Pharmacology, College of Medicine, University of Iowa, Iowa City.
Tedford
C E
CE
Flynn
J R
JR
Yorek
M A
MA
Cannon
J G
JG
Long
J P
JP
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002421:Caudate Nucleus / Q000187:drug effects; D002478:Cells, Cultured; D002794:Choline / Q000493:pharmacokinetics; D006426:Hemicholinium 3 / Q000494:pharmacology*; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D012584:Sciatic Nerve / Q000187:drug effects; D013237:Stereoisomerism
D001713:Biphenyl Compounds; D010880:Piperidines; C057723:1,1'-((1,1'-biphenyl)-4,4'-diylbis(2-hydroxy-2,1-ethanediyl))bis(1,4-dimethylpiperidinium); D006426:Hemicholinium 3; C001771:4,4'-(2-(4-methylpiperidyl)-1-hydroxyethyl)biphenyl; D002794:Choline; D000109:Acetylcholine