TY - JOUR
T1 - Methylpiperidine analog of hemicholinium-3
T2 - A selective, high affinity non-competitive inhibitor of sodium dependent choline uptake system
AU - Chatterjee, Tapan K.
AU - Long, John P.
AU - Cannon, Joseph G.
AU - Bhatnagar, Ranbir K.
N1 - Funding Information:
We wish to thank Dr. Papri Chatterjee and Jeff Six for assistance and Teresa Fulton for typing the manuscript. This work was supported in part by the U.S. Army Medical Research Acquisition Activity, Contract No. DAMD-17-83-C-3010. This paper has been designated as Contribution Number 1818 to the U.S. Army Drug Development Program.
PY - 1988/5/10
Y1 - 1988/5/10
N2 - The potency of hemicholinium-3 (HC-3) and its analogs to inhibit sodium dependent high affinity choline uptake were evaluated in rat striatal synaptosomal preparation. Hemicholinium-3 inhibited sodium dependent high affinity choline uptake (IC50 = 18 nM) while the half molecule of HC-3, HC-15, was inactive. The order of potency for choline uptake inhibition of piperidine substituted HC-3 molecule was as follows: 4-methylpiperidine (A-5 and CA-5) ⋙ HC-3 ≫ unsubstituted piperidines (CA-1 and A-1) ≫ 2- or 3-methylpiperidine (A-2 and A-3) and 4-hydroxypiperidine (A-7). The tertiary amine derivative of 4-methylpiperidine substituted HC-3 (A-4) was nearly 10-fold less potent than its corresponding quaternary derivative (A-5). Choline uptake was inhibited competitively by HC-3 and non-competitively by A-5. The inhibition of choline uptake by A-5 was readily reversible by washing. A-5 did not inhibit the uptake of dopamine and γ-aminobutyric acid. These findings suggest that the N-methyl,4-methylpiperidine analog of HC-3 (A-5) is the most potent of all known inhibitors of sodium dependent high affinity choline uptake and that the inhibition of choline uptake by this compound is mediated through a mechanism distinct from a simple competitive one.
AB - The potency of hemicholinium-3 (HC-3) and its analogs to inhibit sodium dependent high affinity choline uptake were evaluated in rat striatal synaptosomal preparation. Hemicholinium-3 inhibited sodium dependent high affinity choline uptake (IC50 = 18 nM) while the half molecule of HC-3, HC-15, was inactive. The order of potency for choline uptake inhibition of piperidine substituted HC-3 molecule was as follows: 4-methylpiperidine (A-5 and CA-5) ⋙ HC-3 ≫ unsubstituted piperidines (CA-1 and A-1) ≫ 2- or 3-methylpiperidine (A-2 and A-3) and 4-hydroxypiperidine (A-7). The tertiary amine derivative of 4-methylpiperidine substituted HC-3 (A-4) was nearly 10-fold less potent than its corresponding quaternary derivative (A-5). Choline uptake was inhibited competitively by HC-3 and non-competitively by A-5. The inhibition of choline uptake by A-5 was readily reversible by washing. A-5 did not inhibit the uptake of dopamine and γ-aminobutyric acid. These findings suggest that the N-methyl,4-methylpiperidine analog of HC-3 (A-5) is the most potent of all known inhibitors of sodium dependent high affinity choline uptake and that the inhibition of choline uptake by this compound is mediated through a mechanism distinct from a simple competitive one.
KW - Choline uptake
KW - Hemicholinium-3 analogs
KW - Synaptosomes
KW - [H]Hemicholinium-3 binding
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U2 - 10.1016/0014-2999(88)90654-1
DO - 10.1016/0014-2999(88)90654-1
M3 - Article
C2 - 3409952
AN - SCOPUS:0023925654
SN - 0014-2999
VL - 149
SP - 241
EP - 248
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 3
ER -