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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 ?1 and ?2 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 (-)-[(11)C]24b (Ki = 0.78 nM for VAChT, 1200-fold over ? receptors) was successfully synthesized and evaluated in vivo in rats and nonhuman primates. The data revealed that (-)-[(11)C]24b has highest binding in striatum and has favorable pharmacokinetics in the brain.

SUBMITTER: Li J

PROVIDER: S-EPMC3804129 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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

Li Junfeng J Zhang Xiang X Zhang Zhanbin Z Padakanti Prashanth K PK Jin Hongjun H Cui Jinquan J Li Aixiao A Zeng Dexing D Rath Nigam P NP Flores Hubert H Perlmutter Joel S JS Parsons Stanley M SM Tu Zhude Z

Journal of medicinal chemistry 20130718 15

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 ...[more]

PMID: 23802889

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Project description:Invariant E309 is in contact with critical and invariant D398 in a three-dimensional homology model of vesicular acetylcholine transporter (VAChT, TC 2.A.1.2.13) [Vardy, E., et al. (2004) Protein Sci. 13, 1832-1840]. In the work reported here, E309 and D398 in human VAChT were mutated singly and together to test their functions, assign pK values to them, and determine whether the residues are close to each other in three-dimensional space. Mutants were stably expressed in the PC12(A123.7) cell line, and transport and binding properties were characterized at different pH values using radiolabeled ligands and filtration assays. Contrary to a prior conclusion, the results demonstrate that most D398 mutants do not bind the allosteric inhibitor vesamicol even weakly. Earlier work showed that most D398 mutants do not transport ACh. D398 therefore probably is the residue that must deprotonate with a pK of 6.5 for binding of vesamicol and with a pK of approximately 5.9 for transport of ACh. Because E309Q has no effect on VAChT functions at physiological pH, E309 has no apparent critical role. However, radical mutations in E309 cause decreases in ACh and vesamicol affinities and total loss of ACh transport. Unlike wild-type VAChT, which exhibits a peak of [(3)H]vesamicol binding centered at pH 7.4, mutants E309Q, E309D, E309A, and E309K all exhibit peaks of binding centered at pH >or=9. The combination of high pH and mutated E309 apparently produces a relaxed (in contrast to tense) conformation of VAChT that binds vesamicol exceptionally tightly. No compensatory interactions between E309 and D398 in double mutants were discovered. Proof of a close spatial relationship between E309 and D398 was not found. Nevertheless, the data are more consistent with the homology model than an alternative hydropathy model of VAChT that likely locates E309 far from D398 and the ACh binding site in three-dimensional space. Also, a probable network of interactions involving E309 and an unknown residue having a pK of 10 has been revealed.

Dataset Information

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

Publications

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

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