Muscarinic agonist, (±)-quinuclidin-3-yl-(4-fluorophenethyl)(phenyl)carbamate: High affinity, but low subtype selectivity for human M1 – M5 muscarinic acetylcholine receptors
| Autor: | Linda P. Dwoskin, Satheesh Gujarathi, Na-Ra Lee, Kiranbabu Siripurapu, Shobanbabu Bommagani, Guangrong Zheng |
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| Rok vydání: | 2019 |
| Předmět: |
Agonist
Carbamate 010405 organic chemistry Chemistry medicine.drug_class medicine.medical_treatment Chinese hamster ovary cell Organic Chemistry Clinical Biochemistry Antagonist Pharmaceutical Science Pharmacology 01 natural sciences Biochemistry Muscarinic agonist 0104 chemical sciences 010404 medicinal & biomolecular chemistry Dopamine Drug Discovery Muscarinic acetylcholine receptor medicine Oxotremorine Molecular Medicine Molecular Biology medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 29:471-476 |
| ISSN: | 0960-894X |
| Popis: | Novel quinuclidinyl N-phenylcarbamate analogs were synthesized, and binding affinities at M1-M5 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 (Ki = 2.0, 13, 2.6, 2.2, 1.8 nM) at each of the M1-M5 mAChRs, respectively. Based on results from the [3H]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 M3 over M2 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. |
| Databáze: | OpenAIRE |
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