PMID: 3761316Oct 1, 1986Paper

Binding requirements of phenolic phenylethylamines in the benzonorbornene skeleton at the active site of phenylethanolamine N-methyltransferase

Journal of Medicinal Chemistry
Gary L GrunewaldD J Sall

Abstract

In order to determine the active site binding orientation of norepinephrine, a series of conformationally defined analogues of the tyramines, in which the ethylamine side chain is held fixed by incorporation into a benzonorbornene skeleton, were prepared and evaluated for phenylethanolamine N-methyltransferase (PNMT) activity. While exo-2-amino-5- and exo-2-amino-8-hydroxybenzonorbornene (7 and 10, respectively) were prepared from 5-methoxybenzonorbornadiene by azidomercuration/demercuration and reduction, it was necessary to employ both normal (inversion of configuration) and abnormal (retention of configuration) Mitsunobu reactions to prepare, stereoselectively, exo-2-amino-6- and exo-2-amino-7-hydroxybenzonorbornene (8 and 9, respectively) from 6- and 7-methoxybenzonorbornen-2-ol. None of the six analogues were substrates. However, exo-2-amino-6-hydroxybenzonorbornene (8) and anti-9-amino-6-hydroxybenzonorbornene (12) displayed significant activity as inhibitors toward PNMT. The greater potency of 8 and 12, as compared to the parent unsubstituted analogues exo-2-amino- and anti-9-amino-benzonorbornene (4 and 5, respectively), indicates the presence of a spatially compact hydrophilic pocket within the aromatic ring binding re...Continue Reading

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