title: Comparative studies of substrates and inhibitors of choline transport and choline acetyltransferase.
abstract: Analogs of choline and three hemicholinium derivatives were studied as substrates for choline acetyltransferase (ChAc) and as substrates or inhibitors of the high-affinity choline transport system in rat brain synaptosomes. Hemicholiniums-3 and -15, but not terphenylhemicholinium-3, were substrates of ChAc. All three inhibit the high-affinity choline transport system, with I50 values of 0.08, 8.0 and 0.08 muM, respectively. Simple choline analogs with substituents on the beta-carbon atom were found to be very poor substrates for ChAc. N-alkyl analogs, mono-, di- and triethyl choline and N-hydroxyethyl pyrrolidinium methiodide (pyrrolcholine), and DL-alpha-methyl choline are substrates for ChAc and also inhibit choline transport, with I50 values between 2 to 6 muM.[3-H] choline, [3-H] monoethycholine and [3-H] pyrrolcholine were transported into synaptosomes by the choline high affinity system and metabolized to acetyl derivatives. The results indicated that choline transport is the rate-limiting step in the biosynthesis of acetylcholine and provide the basis for the development of a group of cholinergic false transmitters.
mesh_terms: D000123:Acetyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000201:enzymology / Q000648:ultrastructure; D002250:Carbon Radioisotopes; D002794:Choline / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006426:Hemicholinium 3 / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008688:Methacholine Compounds / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D011812:Quinuclidines / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000201:enzymology / Q000378:metabolism*; D014316:Tritium
chemical_list: D002250:Carbon Radioisotopes; D008688:Methacholine Compounds; D011758:Pyrroles; D011759:Pyrrolidines; D011812:Quinuclidines; D014316:Tritium; D006426:Hemicholinium 3; D000123:Acetyltransferases; D002794:Choline