Synthesis and pharmacology of the putative novel muscarinic agonist (S)- 4-F-MePyMcN [(S)-4-(pyrrolidino)-1-methyl-2-butynyl-N-(4-fluorophenyl) carbamate oxalate]

Saleh Athmani, Karen N. Bradley, Alan L. Harvey, Edgar Kornisiuk, Diana Jerusalinsky

Research output: Contribution to journalArticle

Abstract

(S)-4-F-MePyMcN [(S)-4-(pyrrolidino)-1-methyl-2-butynyl-N-(4- fluorophenyl) carbamate oxalate] has been suggested to be a selective agonist at the M1 subtype of muscarinic receptor [Lambrecht G. et al., Life Sci. 56 (1995) 815-822]. We synthesized the compound and tested its selectivity for different muscarinic receptors with binding experiments using rat cerebral cortex synaptosomal membranes and cloned human ml to m5 receptors and by functional experiments on rabbit vas deferens preparations. There was little difference in affinity for the compound at the different cloned muscarinic receptors (IC50s for displacement of 3H-N-methylscopolamine were 0.7-1.0 μM). On rabbit vas deferens preparations, (S)-4-F-MePyMcN did reduce twitch responses to electrical stimulation like the known M1 agonist McN-A-343, but unlike McN-A-343 the compound reduced postsynaptic sensitivity to noradrenaline, ATP and KCl. Because of these additional actions, (S)-4-F- MePyMcN may not be suitable as a tool to study M1 muscarinic receptors selectively.

Original languageEnglish
Pages (from-to)935-941
Number of pages7
JournalEuropean Journal of Medicinal Chemistry
Volume33
Issue number12
DOIs
Publication statusPublished - 31 Dec 1998

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(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride
Muscarinic M1 Receptors
Muscarinic Agonists
Carbamates
Vas Deferens
Oxalates
Muscarinic Receptors
N-Methylscopolamine
Pharmacology
Rabbits
Cerebral Cortex
Electric Stimulation
Norepinephrine
Adenosine Triphosphate
Membranes
Rats
Experiments

Keywords

  • ligand binding
  • McN-A-343
  • muscarinic receptors
  • N- methylscopolamine
  • selective agonists

Cite this

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title = "Synthesis and pharmacology of the putative novel muscarinic agonist (S)- 4-F-MePyMcN [(S)-4-(pyrrolidino)-1-methyl-2-butynyl-N-(4-fluorophenyl) carbamate oxalate]",
abstract = "(S)-4-F-MePyMcN [(S)-4-(pyrrolidino)-1-methyl-2-butynyl-N-(4- fluorophenyl) carbamate oxalate] has been suggested to be a selective agonist at the M1 subtype of muscarinic receptor [Lambrecht G. et al., Life Sci. 56 (1995) 815-822]. We synthesized the compound and tested its selectivity for different muscarinic receptors with binding experiments using rat cerebral cortex synaptosomal membranes and cloned human ml to m5 receptors and by functional experiments on rabbit vas deferens preparations. There was little difference in affinity for the compound at the different cloned muscarinic receptors (IC50s for displacement of 3H-N-methylscopolamine were 0.7-1.0 μM). On rabbit vas deferens preparations, (S)-4-F-MePyMcN did reduce twitch responses to electrical stimulation like the known M1 agonist McN-A-343, but unlike McN-A-343 the compound reduced postsynaptic sensitivity to noradrenaline, ATP and KCl. Because of these additional actions, (S)-4-F- MePyMcN may not be suitable as a tool to study M1 muscarinic receptors selectively.",
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Synthesis and pharmacology of the putative novel muscarinic agonist (S)- 4-F-MePyMcN [(S)-4-(pyrrolidino)-1-methyl-2-butynyl-N-(4-fluorophenyl) carbamate oxalate]. / Athmani, Saleh; Bradley, Karen N.; Harvey, Alan L.; Kornisiuk, Edgar; Jerusalinsky, Diana.

In: European Journal of Medicinal Chemistry, Vol. 33, No. 12, 31.12.1998, p. 935-941.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Synthesis and pharmacology of the putative novel muscarinic agonist (S)- 4-F-MePyMcN [(S)-4-(pyrrolidino)-1-methyl-2-butynyl-N-(4-fluorophenyl) carbamate oxalate]

AU - Athmani, Saleh

AU - Bradley, Karen N.

AU - Harvey, Alan L.

AU - Kornisiuk, Edgar

AU - Jerusalinsky, Diana

PY - 1998/12/31

Y1 - 1998/12/31

N2 - (S)-4-F-MePyMcN [(S)-4-(pyrrolidino)-1-methyl-2-butynyl-N-(4- fluorophenyl) carbamate oxalate] has been suggested to be a selective agonist at the M1 subtype of muscarinic receptor [Lambrecht G. et al., Life Sci. 56 (1995) 815-822]. We synthesized the compound and tested its selectivity for different muscarinic receptors with binding experiments using rat cerebral cortex synaptosomal membranes and cloned human ml to m5 receptors and by functional experiments on rabbit vas deferens preparations. There was little difference in affinity for the compound at the different cloned muscarinic receptors (IC50s for displacement of 3H-N-methylscopolamine were 0.7-1.0 μM). On rabbit vas deferens preparations, (S)-4-F-MePyMcN did reduce twitch responses to electrical stimulation like the known M1 agonist McN-A-343, but unlike McN-A-343 the compound reduced postsynaptic sensitivity to noradrenaline, ATP and KCl. Because of these additional actions, (S)-4-F- MePyMcN may not be suitable as a tool to study M1 muscarinic receptors selectively.

AB - (S)-4-F-MePyMcN [(S)-4-(pyrrolidino)-1-methyl-2-butynyl-N-(4- fluorophenyl) carbamate oxalate] has been suggested to be a selective agonist at the M1 subtype of muscarinic receptor [Lambrecht G. et al., Life Sci. 56 (1995) 815-822]. We synthesized the compound and tested its selectivity for different muscarinic receptors with binding experiments using rat cerebral cortex synaptosomal membranes and cloned human ml to m5 receptors and by functional experiments on rabbit vas deferens preparations. There was little difference in affinity for the compound at the different cloned muscarinic receptors (IC50s for displacement of 3H-N-methylscopolamine were 0.7-1.0 μM). On rabbit vas deferens preparations, (S)-4-F-MePyMcN did reduce twitch responses to electrical stimulation like the known M1 agonist McN-A-343, but unlike McN-A-343 the compound reduced postsynaptic sensitivity to noradrenaline, ATP and KCl. Because of these additional actions, (S)-4-F- MePyMcN may not be suitable as a tool to study M1 muscarinic receptors selectively.

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