Muscarinic agonist, (±)-quinuclidin-3-yl-(4-fluorophenethyl)(phenyl)carbamate: High affinity, but low subtype selectivity for human M 1 – M 5 muscarinic acetylcholine receptors

Na Ra Lee, Satheesh Gujarathi, Shobanbabu Bommagani, Kiranbabu Siripurapu, Guangrong Zheng, Linda P. Dwoskin

Research output: Contribution to journalArticlepeer-review

Abstract

Novel quinuclidinyl N-phenylcarbamate analogs were synthesized, and binding affinities at M 1 -M 5 muscarinic acetylcholine receptor (mAChR) subtypes were determined using Chinese hamster ovary (CHO) cell membranes stably expressing one specific subtype of human mAChR. Although not subtype selective, the lead analog (±)-quinuclidin-3-yl-(4-fluorophenethyl)(phenyl)carbamate (3c) exhibited the highest affinity (K i = 2.0, 13, 2.6, 2.2, 1.8 nM) at each of the M 1 -M 5 mAChRs, respectively. Based on results from the [ 3 H]dopamine release assay using rat striatal slices, 3c acted as an agonist at mAChRs. The effect of 3c was inhibited by the nonselective mAChR antagonist, scopolamine, and 3c augmented release evoked by oxotremorine. A potent analog from the same scaffold, (±)-quinuclidin-3-yl-(4-methoxyphenethyl)(phenyl)-carbamate (3b) exhibited the greatest selectivity (17-fold) at M 3 over M 2 mAChRs. These analogs could serve as leads for further discovery of novel subtype-selective muscarinic ligands with the goal of providing therapeutics for substance use disorders and chronic obstructive pulmonary disease.

Original languageEnglish
Pages (from-to)471-476
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume29
Issue number3
DOIs
StatePublished - Feb 1 2019

Bibliographical note

Funding Information:
This work was supported by funding from the National Institute of Health including grants DA 030667 and UL1 TR001998 .

Publisher Copyright:
© 2018 Elsevier Ltd

Keywords

  • Carbamate
  • Chronic obstructive pulmonary disease
  • Muscarinic acetylcholine receptors
  • Substance use disorders
  • [ H]N-methylscopolamine binding
  • [ H]dopamine release

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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