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

doi:10.1016/j.bmcl.2018.12.022

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 journal › Article › peer-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 language	English
Pages (from-to)	471-476
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	29
Issue number	3
DOIs	https://doi.org/10.1016/j.bmcl.2018.12.022
State	Published - Feb 1 2019

Bibliographical note

Publisher Copyright:
© 2018 Elsevier Ltd

Funding

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

Funders	Funder number
National Institutes of Health (NIH)	UL1 TR001998
National Institutes of Health (NIH)
National Institute on Drug Abuse	R21DA030667
National Institute on Drug Abuse

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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

Access to Document

10.1016/j.bmcl.2018.12.022

Cite this

Lee, N. R., Gujarathi, S., Bommagani, S., Siripurapu, K., Zheng, G., & Dwoskin, L. P. (2019). Muscarinic agonist, (±)-quinuclidin-3-yl-(4-fluorophenethyl)(phenyl)carbamate: High affinity, but low subtype selectivity for human M ₁ – M ₅ muscarinic acetylcholine receptors. Bioorganic and Medicinal Chemistry Letters, 29(3), 471-476. https://doi.org/10.1016/j.bmcl.2018.12.022

Lee, Na Ra ; Gujarathi, Satheesh ; Bommagani, Shobanbabu et al. / Muscarinic agonist, (±)-quinuclidin-3-yl-(4-fluorophenethyl)(phenyl)carbamate : High affinity, but low subtype selectivity for human M ₁ – M ₅ muscarinic acetylcholine receptors. In: Bioorganic and Medicinal Chemistry Letters. 2019 ; Vol. 29, No. 3. pp. 471-476.

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

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.",

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

author = "Lee, \{Na Ra\} and Satheesh Gujarathi and Shobanbabu Bommagani and Kiranbabu Siripurapu and Guangrong Zheng and Dwoskin, \{Linda P.\}",

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Lee, NR, Gujarathi, S, Bommagani, S, Siripurapu, K, Zheng, G & Dwoskin, LP 2019, 'Muscarinic agonist, (±)-quinuclidin-3-yl-(4-fluorophenethyl)(phenyl)carbamate: High affinity, but low subtype selectivity for human M ₁ – M ₅ muscarinic acetylcholine receptors', Bioorganic and Medicinal Chemistry Letters, vol. 29, no. 3, pp. 471-476. https://doi.org/10.1016/j.bmcl.2018.12.022

Muscarinic agonist, (±)-quinuclidin-3-yl-(4-fluorophenethyl)(phenyl)carbamate: High affinity, but low subtype selectivity for human M ₁ – M ₅ muscarinic acetylcholine receptors. / Lee, Na Ra; Gujarathi, Satheesh; Bommagani, Shobanbabu et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 29, No. 3, 01.02.2019, p. 471-476.

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

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T1 - Muscarinic agonist, (±)-quinuclidin-3-yl-(4-fluorophenethyl)(phenyl)carbamate

T2 - High affinity, but low subtype selectivity for human M 1 – M 5 muscarinic acetylcholine receptors

AU - Lee, Na Ra

AU - Gujarathi, Satheesh

AU - Bommagani, Shobanbabu

AU - Siripurapu, Kiranbabu

AU - Zheng, Guangrong

AU - Dwoskin, Linda P.

PY - 2019/2/1

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N2 - 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.

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KW - Carbamate

KW - Chronic obstructive pulmonary disease

KW - Muscarinic acetylcholine receptors

KW - Substance use disorders

KW - [ H]N-methylscopolamine binding

KW - [ H]dopamine release

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Lee NR, Gujarathi S, Bommagani S, Siripurapu K, Zheng G, Dwoskin LP. Muscarinic agonist, (±)-quinuclidin-3-yl-(4-fluorophenethyl)(phenyl)carbamate: High affinity, but low subtype selectivity for human M ₁ – M ₅ muscarinic acetylcholine receptors. Bioorganic and Medicinal Chemistry Letters. 2019 Feb 1;29(3):471-476. doi: 10.1016/j.bmcl.2018.12.022