Heteroaromatic and aniline derivatives of piperidines as potent ligands for vesicular acetylcholine transporter

Junfeng Li; Xiang Zhang; Zhanbin Zhang; Prashanth K. Padakanti; Hongjun Jin; Jinquan Cui; Aixiao Li; Dexing Zeng; Nigam P. Rath; Hubert Flores; Joel S. Perlmutter; Stanley M. Parsons; Zhude Tu

doi:10.1021/jm400664x

Heteroaromatic and aniline derivatives of piperidines as potent ligands for vesicular acetylcholine transporter

Junfeng Li, Xiang Zhang, Zhanbin Zhang, Prashanth K. Padakanti, Hongjun Jin, Jinquan Cui, Aixiao Li, Dexing Zeng, Nigam P. Rath, Hubert Flores, Joel S. Perlmutter, Stanley M. Parsons, Zhude Tu

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

Abstract

To identify suitable lipophilic compounds having high potency and selectivity for vesicular acetylcholine transporter (VAChT), a heteroaromatic ring or a phenyl group was introduced into the carbonyl-containing scaffold for VAChT ligands. Twenty new compounds with ALogD values between 0.53 and 3.2 were synthesized, and their in vitro binding affinities were assayed. Six of them (19a, 19e, 19g, 19k, and 24a-b) displayed high affinity for VAChT (K_i = 0.93-18 nM for racemates) and moderate to high selectivity for VAChT over σ₁ and σ₂ receptors (K_i = 44-4400-fold). These compounds have a methyl or a fluoro substitution that provides the position for incorporating PET radioisotopes C-11 or F-18. Compound (-)-[¹¹C]24b (K_i = 0.78 nM for VAChT, 1200-fold over σ receptors) was successfully synthesized and evaluated in vivo in rats and nonhuman primates. The data revealed that (-)-[¹¹C]24b has highest binding in striatum and has favorable pharmacokinetics in the brain.

Original language	English (US)
Pages (from-to)	6216-6233
Number of pages	18
Journal	Journal of Medicinal Chemistry
Volume	56
Issue number	15
DOIs	https://doi.org/10.1021/jm400664x
State	Published - Aug 8 2013
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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title = "Heteroaromatic and aniline derivatives of piperidines as potent ligands for vesicular acetylcholine transporter",

abstract = "To identify suitable lipophilic compounds having high potency and selectivity for vesicular acetylcholine transporter (VAChT), a heteroaromatic ring or a phenyl group was introduced into the carbonyl-containing scaffold for VAChT ligands. Twenty new compounds with ALogD values between 0.53 and 3.2 were synthesized, and their in vitro binding affinities were assayed. Six of them (19a, 19e, 19g, 19k, and 24a-b) displayed high affinity for VAChT (Ki = 0.93-18 nM for racemates) and moderate to high selectivity for VAChT over σ1 and σ2 receptors (Ki = 44-4400-fold). These compounds have a methyl or a fluoro substitution that provides the position for incorporating PET radioisotopes C-11 or F-18. Compound (-)-[11C]24b (Ki = 0.78 nM for VAChT, 1200-fold over σ receptors) was successfully synthesized and evaluated in vivo in rats and nonhuman primates. The data revealed that (-)-[11C]24b has highest binding in striatum and has favorable pharmacokinetics in the brain.",

author = "Junfeng Li and Xiang Zhang and Zhanbin Zhang and Padakanti, {Prashanth K.} and Hongjun Jin and Jinquan Cui and Aixiao Li and Dexing Zeng and Rath, {Nigam P.} and Hubert Flores and Perlmutter, {Joel S.} and Parsons, {Stanley M.} and Zhude Tu",

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doi = "10.1021/jm400664x",

language = "English (US)",

volume = "56",

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AU - Li, Junfeng

AU - Zhang, Xiang

AU - Zhang, Zhanbin

AU - Padakanti, Prashanth K.

AU - Jin, Hongjun

AU - Cui, Jinquan

AU - Li, Aixiao

AU - Zeng, Dexing

AU - Rath, Nigam P.

AU - Flores, Hubert

AU - Perlmutter, Joel S.

AU - Parsons, Stanley M.

AU - Tu, Zhude

PY - 2013/8/8

Y1 - 2013/8/8

N2 - To identify suitable lipophilic compounds having high potency and selectivity for vesicular acetylcholine transporter (VAChT), a heteroaromatic ring or a phenyl group was introduced into the carbonyl-containing scaffold for VAChT ligands. Twenty new compounds with ALogD values between 0.53 and 3.2 were synthesized, and their in vitro binding affinities were assayed. Six of them (19a, 19e, 19g, 19k, and 24a-b) displayed high affinity for VAChT (Ki = 0.93-18 nM for racemates) and moderate to high selectivity for VAChT over σ1 and σ2 receptors (Ki = 44-4400-fold). These compounds have a methyl or a fluoro substitution that provides the position for incorporating PET radioisotopes C-11 or F-18. Compound (-)-[11C]24b (Ki = 0.78 nM for VAChT, 1200-fold over σ receptors) was successfully synthesized and evaluated in vivo in rats and nonhuman primates. The data revealed that (-)-[11C]24b has highest binding in striatum and has favorable pharmacokinetics in the brain.

AB - To identify suitable lipophilic compounds having high potency and selectivity for vesicular acetylcholine transporter (VAChT), a heteroaromatic ring or a phenyl group was introduced into the carbonyl-containing scaffold for VAChT ligands. Twenty new compounds with ALogD values between 0.53 and 3.2 were synthesized, and their in vitro binding affinities were assayed. Six of them (19a, 19e, 19g, 19k, and 24a-b) displayed high affinity for VAChT (Ki = 0.93-18 nM for racemates) and moderate to high selectivity for VAChT over σ1 and σ2 receptors (Ki = 44-4400-fold). These compounds have a methyl or a fluoro substitution that provides the position for incorporating PET radioisotopes C-11 or F-18. Compound (-)-[11C]24b (Ki = 0.78 nM for VAChT, 1200-fold over σ receptors) was successfully synthesized and evaluated in vivo in rats and nonhuman primates. The data revealed that (-)-[11C]24b has highest binding in striatum and has favorable pharmacokinetics in the brain.

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Heteroaromatic and aniline derivatives of piperidines as potent ligands for vesicular acetylcholine transporter

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