Importance of the aromatic ring in adrenergic amines. 5. Nonaromatic analogs of phenylethanolamine as inhibitors of phenylethanolamine N-methyltransferase: role of hydrophobic and steric interactions

Journal of Medicinal Chemistry
1981.0

Abstract

The synthesis of five classes [type A, cycloalkylethanolamines; type B, n-alkylethanolamines; type C, 2-(aminomethyl)-2-n-alkanols; type D, 1-(aminomethyl)cycloalkanols; type E, sec-alkylethanolamines] of nonaromatic analogues of β-phenylethanolamine and an evaluation of their inhibitory potency (IC₅₀) for phenylethanolamine N-methyltransferase (PNMT) are described. The key intermediates for the synthesis of the ethanolamines were the appropriate aldehydes or ketones. Type A aldehydes 11a (cyclobutyl) and 13a (cycloheptyl) were prepared from corresponding acids via reduction to alcohols with lithium aluminum hydride (LiAlH₄) and oxidation to aldehydes with pyridinium chlorochromate (PCC). Aldehydes 15a (cycloundecyl) and 41a (adamantyl) of type A were obtained by oxidizing corresponding alcohols with PCC. Cyclononanecarboxaldehyde (type A, 14a) was synthesized via a multistep route starting with Favorskii rearrangement of 2-bromocyclodecanone to cyclononanecarboxylic acid, followed by LiAlH₄ reduction to the alcohol and PCC oxidation to the aldehyde. Aldehydes or ketones were converted to cyanohydrin ethers with trimethylsilyl cyanide, then reduced to target ethanolamines using LiAlH₄. The ethanolamines were tested as PNMT inhibitors via the LCEC assay. The most potent inhibitors were type A compounds 8 (cyclooctyl), 13c (cycloheptyl), 14c (cyclononyl), 15c (cycloundecyl) and type D compounds 26c (cyclononyl), 27c (cycloundecyl) with IC₅₀ values ranging from 6 to 17 μM. It is concluded that the PNMT binding site accepts hydrophobic groups with optimal length (~6.4 Å) and width (~2.5 Å), has significant height restriction, and the ethanolamine side chain prefers to lie away from and along the longitudinal axis of the hydrophobic group. Ethanolamines with an ethanolamine side chain attached to a cycloalkyl ring (types A and D) are considerably more potent inhibitors of PNMT than open-chain compounds (types B, C, E) with the same total number of carbon atoms.

Knowledge Graph

Similar Paper

Importance of the aromatic ring in adrenergic amines. 5. Nonaromatic analogs of phenylethanolamine as inhibitors of phenylethanolamine N-methyltransferase: role of hydrophobic and steric interactions
Journal of Medicinal Chemistry 1981.0
Importance of the aromatic ring in adrenergic amines. 7. Comparison of the stereoselectivity of norepinephrine N-methyltransferase for aromatics. Nonaromatic substrates and inhibitors
Journal of Medicinal Chemistry 1982.0
Conformationally defined adrenergic agents. 15. Conformationally restricted and conformationally defined tyramine analogs as inhibitors of phenylethanolamine N-methyltransferase
Journal of Medicinal Chemistry 1989.0
Conformational requirements of substrates for activity with phenylethanolamine N-methyltransferase
Journal of Medicinal Chemistry 1988.0
Stereochemical aspects of phenylethanolamine analogs as substrates of phenylethanolamine N-methyltransferase
Journal of Medicinal Chemistry 1988.0
Conformational preference for the binding of biaryl substrates and inhibitors to the active site of phenylethanolamine N-methyltransferase (PNMT)
Journal of Medicinal Chemistry 1988.0
Molecular Recognition of Sub-micromolar Inhibitors by the Epinephrine-Synthesizing Enzyme Phenylethanolamine N-Methyltransferase
Journal of Medicinal Chemistry 2004.0
Inhibition of phenylethanolamine N-methyltransferase (PNMT) by aromatic hydroxy-substituted 1,2,3,4-tetrahydroisoquinolines. Further studies on the hydrophilic pocket of the aromatic ring binding region of the active site
Journal of Medicinal Chemistry 1987.0
Effect of Ring Size or an Additional Heteroatom on the Potency and Selectivity of Bicyclic Benzylamine-Type Inhibitors of PhenylethanolamineN-Methyltransferase<sup>1a</sup>
Journal of Medicinal Chemistry 1996.0
Conformationally defined adrenergic agents. 13. Conformational and steric aspects of the inhibition of phenylethanolamine N-methyltransferase by benzylamines
Journal of Medicinal Chemistry 1988.0