Lithocholylcholine, a bile acid/acetylcholine hybrid, is a muscarinic receptor antagonist

Kunrong Cheng, Sandeep Khurana, Ying Chen, Richard H. Kennedy, Piotr Zimniak, Jean Pierre Raufman

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Previous work from our laboratory indicates that bile acids, specifically lithocholic acid conjugates, interact with muscarinic receptors on gastric chief cells. Structural similarities between acetylcholine and lithocholyltaurine suggest a potential molecular basis for their interaction with the same receptor. We synthesized a hybrid molecule consisting of the steroid nucleus of lithocholyltaurine and the choline moiety of acetylcholine. The new molecule, lithocholylcholine, is hydrolyzed by acetylcholinesterase. Lithocholylcholine inhibited binding of a cholinergic radioligand to Chinese hamster ovary cells expressing each of the five muscarinic receptor subtypes. The binding affinities (K1; micromolar) of lithocholylcholine for these receptors were: M3 (1.0) > M1 (2.7) > M2 (4.1) = M4 (4.9) > M5 (6.2). Lithocholylcholine inhibited intracellular signaling pathways mediated by interaction with M1, M2, and M3 muscarinic receptors. Regarding M3 receptors, lithocholylcholine was 10-fold more potent than lithocholyltaurine in terms of binding affinity and inhibition of acetylcholine-induced increases in inositol phosphate formation and mitogen-activated protein kinase phosphorylation. In a functional assay, lithocholylcholine inhibited acetylcholine-induced relaxation of rat aortic rings. These observations indicate that lithocholylcholine is a muscarinic receptor antagonist and provide further evidence that bile acids may have gastrointestinal signaling functions that extend beyond their effects on sterol metabolism, lipid absorption, and cholesterol elimination. Hybrid molecules created from bile acids and acetylcholine may be used to develop selective muscarinic receptor ligands.

Original languageEnglish (US)
Pages (from-to)29-35
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume303
Issue number1
DOIs
StatePublished - Oct 1 2002

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Muscarinic Antagonists
Muscarinic Receptors
Bile Acids and Salts
Acetylcholine
Taurolithocholic Acid
Gastric Chief Cells
Muscarinic M3 Receptors
Lithocholic Acid
Muscarinic M2 Receptors
Muscarinic M1 Receptors
Inositol Phosphates
Sterols
Acetylcholinesterase
Choline
Cricetulus
lithocholylcholine
Mitogen-Activated Protein Kinases
Lipid Metabolism
Cholinergic Agents
Ovary

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Lithocholylcholine, a bile acid/acetylcholine hybrid, is a muscarinic receptor antagonist. / Cheng, Kunrong; Khurana, Sandeep; Chen, Ying; Kennedy, Richard H.; Zimniak, Piotr; Raufman, Jean Pierre.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 303, No. 1, 01.10.2002, p. 29-35.

Research output: Contribution to journalArticle

Cheng, Kunrong ; Khurana, Sandeep ; Chen, Ying ; Kennedy, Richard H. ; Zimniak, Piotr ; Raufman, Jean Pierre. / Lithocholylcholine, a bile acid/acetylcholine hybrid, is a muscarinic receptor antagonist. In: Journal of Pharmacology and Experimental Therapeutics. 2002 ; Vol. 303, No. 1. pp. 29-35.
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