Comparative studies of substrates and inhibitors of choline transport and choline acetyltransferase.

TLDR

The study examined choline analogs and hemicholinium derivatives as substrates for choline acetyltransferase and as substrates or inhibitors of the high‑affinity choline transport system in rat brain synaptosomes. Hemicholiniums‑3 and ‑15 act as substrates for choline acetyltransferase while all three hemicholinium derivatives inhibit the high‑affinity choline transport system (I50 = 0.08–8 µM); simple beta‑carbon substituted analogs are poor substrates, whereas N‑alkyl, mono‑, di‑ and tri‑ethyl choline derivatives and pyrrolcholine are both substrates and inhibitors (I50 = 2–6 µM), and labeled analogs are transported and acetylated, confirming that choline transport limits acetylcholine synthesis and supporting the development of cholinergic false transmitters.

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.