Conformationally restricted and conformationally defined tyramine analogues as inhibitors of phenylethanolamine N-methyltransferase

Qizhuang Ye, Gary L. Grunewald

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Abstract

In a search for a selective inhibitor for the epinephrine synthesizing enzyme phenylethanolamine N-methyltransferase (PNMT; EC 2.1.1.28), phenolic 2-aminotetralins (12-15 as conformationally restricted analogues of tyramine) and phenolic benzobicyclo[3.2.1]octylamines (22-24 as conformationally defined analogues of tyramine) were used to gain information about the binding interactions of the catecholic hydroxyl groups in the natural substrate norepinephrine at the active site of PNMT. In addition, these analogues provided information about the effects of conformational flexibility on active-site interaction of the aminoethyl side chain in phenolic phenylethylamines that may aid in learning the manner in which norepinephrine binds at the active site of PNMT. Analogues 22-24 were synthesized by a nine-step sequence, in which a Friedel-Crafts type intramolecular cyclization was the key step in the construction of the benzobicyclo[3.2.1]octane skeleton. p-Tyramine (10, Ki = 294 μM) was more potent than phenylethylamine (1, Ki = 854 μM) but m-tyramine (9, Ki = 1250 μM) was less potent than phenylethylamine as an inhibitor of PNMT. Similarly, in the conformationally restricted and conformationally defined tyramine analogues (12-15 and 22-24, respectively), the analogues with the p-tyramine moiety (14, Ki = 4.7 μM; 23, Ki = 111 μM) bind to PNMT better than do the corresponding unsubstituted compounds (16, Ki = 6.8 μM; 25, Ki = 206 μM) while the analogues with the m-tyramine moiety (13,15, 22, and 24) have a lower binding affinity than do 16 and 25. The greatly enhanced activity of the phenolic 2-aminotetralins (12-15) compared with m- and p-tyramine (9 and 10, respectively) is likely due to the restriction of the side-chain conformation. The conformationally defined analogues 22-24 were less active than the comformationally restricted ones, 12-15, although the low-energy half-chair conformation of 2-aminotetralin is defined in 22-24. The reduced activity of 22-24 compared with the activity of 12-15 is probably due to the steric hindrance from the extra bridging atoms in binding to PNMT. The interaction of the p-hydroxyl group of the tyramine moiety may involve hydrogen bonding since the corrresponding methyl ethers show a greatly reduced affinity for the active site of PNMT (Ki = 34 and 389 μM for methoxy analogues 28 and 35, compared to Ki = 4.7 and 111 μM for the corresponding phenolic analogues 14 and 23).

Original languageEnglish (US)
Pages (from-to)478-486
Number of pages9
JournalJournal of Medicinal Chemistry
Volume32
Issue number2
StatePublished - 1989
Externally publishedYes

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Phenylethanolamine N-Methyltransferase
Tyramine
Phenethylamines
Catalytic Domain
Hydroxyl Radical
Conformations
Norepinephrine
Methyl Ethers
Cyclization
Hydrogen Bonding
Skeleton
Epinephrine
Hydrogen bonds
Learning
Atoms
Substrates
Enzymes

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

@article{38db60505f364cba83bd61e6ecc78319,
title = "Conformationally restricted and conformationally defined tyramine analogues as inhibitors of phenylethanolamine N-methyltransferase",
abstract = "In a search for a selective inhibitor for the epinephrine synthesizing enzyme phenylethanolamine N-methyltransferase (PNMT; EC 2.1.1.28), phenolic 2-aminotetralins (12-15 as conformationally restricted analogues of tyramine) and phenolic benzobicyclo[3.2.1]octylamines (22-24 as conformationally defined analogues of tyramine) were used to gain information about the binding interactions of the catecholic hydroxyl groups in the natural substrate norepinephrine at the active site of PNMT. In addition, these analogues provided information about the effects of conformational flexibility on active-site interaction of the aminoethyl side chain in phenolic phenylethylamines that may aid in learning the manner in which norepinephrine binds at the active site of PNMT. Analogues 22-24 were synthesized by a nine-step sequence, in which a Friedel-Crafts type intramolecular cyclization was the key step in the construction of the benzobicyclo[3.2.1]octane skeleton. p-Tyramine (10, Ki = 294 μM) was more potent than phenylethylamine (1, Ki = 854 μM) but m-tyramine (9, Ki = 1250 μM) was less potent than phenylethylamine as an inhibitor of PNMT. Similarly, in the conformationally restricted and conformationally defined tyramine analogues (12-15 and 22-24, respectively), the analogues with the p-tyramine moiety (14, Ki = 4.7 μM; 23, Ki = 111 μM) bind to PNMT better than do the corresponding unsubstituted compounds (16, Ki = 6.8 μM; 25, Ki = 206 μM) while the analogues with the m-tyramine moiety (13,15, 22, and 24) have a lower binding affinity than do 16 and 25. The greatly enhanced activity of the phenolic 2-aminotetralins (12-15) compared with m- and p-tyramine (9 and 10, respectively) is likely due to the restriction of the side-chain conformation. The conformationally defined analogues 22-24 were less active than the comformationally restricted ones, 12-15, although the low-energy half-chair conformation of 2-aminotetralin is defined in 22-24. The reduced activity of 22-24 compared with the activity of 12-15 is probably due to the steric hindrance from the extra bridging atoms in binding to PNMT. The interaction of the p-hydroxyl group of the tyramine moiety may involve hydrogen bonding since the corrresponding methyl ethers show a greatly reduced affinity for the active site of PNMT (Ki = 34 and 389 μM for methoxy analogues 28 and 35, compared to Ki = 4.7 and 111 μM for the corresponding phenolic analogues 14 and 23).",
author = "Qizhuang Ye and Grunewald, {Gary L.}",
year = "1989",
language = "English (US)",
volume = "32",
pages = "478--486",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "2",

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TY - JOUR

T1 - Conformationally restricted and conformationally defined tyramine analogues as inhibitors of phenylethanolamine N-methyltransferase

AU - Ye, Qizhuang

AU - Grunewald, Gary L.

PY - 1989

Y1 - 1989

N2 - In a search for a selective inhibitor for the epinephrine synthesizing enzyme phenylethanolamine N-methyltransferase (PNMT; EC 2.1.1.28), phenolic 2-aminotetralins (12-15 as conformationally restricted analogues of tyramine) and phenolic benzobicyclo[3.2.1]octylamines (22-24 as conformationally defined analogues of tyramine) were used to gain information about the binding interactions of the catecholic hydroxyl groups in the natural substrate norepinephrine at the active site of PNMT. In addition, these analogues provided information about the effects of conformational flexibility on active-site interaction of the aminoethyl side chain in phenolic phenylethylamines that may aid in learning the manner in which norepinephrine binds at the active site of PNMT. Analogues 22-24 were synthesized by a nine-step sequence, in which a Friedel-Crafts type intramolecular cyclization was the key step in the construction of the benzobicyclo[3.2.1]octane skeleton. p-Tyramine (10, Ki = 294 μM) was more potent than phenylethylamine (1, Ki = 854 μM) but m-tyramine (9, Ki = 1250 μM) was less potent than phenylethylamine as an inhibitor of PNMT. Similarly, in the conformationally restricted and conformationally defined tyramine analogues (12-15 and 22-24, respectively), the analogues with the p-tyramine moiety (14, Ki = 4.7 μM; 23, Ki = 111 μM) bind to PNMT better than do the corresponding unsubstituted compounds (16, Ki = 6.8 μM; 25, Ki = 206 μM) while the analogues with the m-tyramine moiety (13,15, 22, and 24) have a lower binding affinity than do 16 and 25. The greatly enhanced activity of the phenolic 2-aminotetralins (12-15) compared with m- and p-tyramine (9 and 10, respectively) is likely due to the restriction of the side-chain conformation. The conformationally defined analogues 22-24 were less active than the comformationally restricted ones, 12-15, although the low-energy half-chair conformation of 2-aminotetralin is defined in 22-24. The reduced activity of 22-24 compared with the activity of 12-15 is probably due to the steric hindrance from the extra bridging atoms in binding to PNMT. The interaction of the p-hydroxyl group of the tyramine moiety may involve hydrogen bonding since the corrresponding methyl ethers show a greatly reduced affinity for the active site of PNMT (Ki = 34 and 389 μM for methoxy analogues 28 and 35, compared to Ki = 4.7 and 111 μM for the corresponding phenolic analogues 14 and 23).

AB - In a search for a selective inhibitor for the epinephrine synthesizing enzyme phenylethanolamine N-methyltransferase (PNMT; EC 2.1.1.28), phenolic 2-aminotetralins (12-15 as conformationally restricted analogues of tyramine) and phenolic benzobicyclo[3.2.1]octylamines (22-24 as conformationally defined analogues of tyramine) were used to gain information about the binding interactions of the catecholic hydroxyl groups in the natural substrate norepinephrine at the active site of PNMT. In addition, these analogues provided information about the effects of conformational flexibility on active-site interaction of the aminoethyl side chain in phenolic phenylethylamines that may aid in learning the manner in which norepinephrine binds at the active site of PNMT. Analogues 22-24 were synthesized by a nine-step sequence, in which a Friedel-Crafts type intramolecular cyclization was the key step in the construction of the benzobicyclo[3.2.1]octane skeleton. p-Tyramine (10, Ki = 294 μM) was more potent than phenylethylamine (1, Ki = 854 μM) but m-tyramine (9, Ki = 1250 μM) was less potent than phenylethylamine as an inhibitor of PNMT. Similarly, in the conformationally restricted and conformationally defined tyramine analogues (12-15 and 22-24, respectively), the analogues with the p-tyramine moiety (14, Ki = 4.7 μM; 23, Ki = 111 μM) bind to PNMT better than do the corresponding unsubstituted compounds (16, Ki = 6.8 μM; 25, Ki = 206 μM) while the analogues with the m-tyramine moiety (13,15, 22, and 24) have a lower binding affinity than do 16 and 25. The greatly enhanced activity of the phenolic 2-aminotetralins (12-15) compared with m- and p-tyramine (9 and 10, respectively) is likely due to the restriction of the side-chain conformation. The conformationally defined analogues 22-24 were less active than the comformationally restricted ones, 12-15, although the low-energy half-chair conformation of 2-aminotetralin is defined in 22-24. The reduced activity of 22-24 compared with the activity of 12-15 is probably due to the steric hindrance from the extra bridging atoms in binding to PNMT. The interaction of the p-hydroxyl group of the tyramine moiety may involve hydrogen bonding since the corrresponding methyl ethers show a greatly reduced affinity for the active site of PNMT (Ki = 34 and 389 μM for methoxy analogues 28 and 35, compared to Ki = 4.7 and 111 μM for the corresponding phenolic analogues 14 and 23).

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