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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 region of the active site of the enzyme. Furthermore, the greater activity of 12, relative to 8, is consistent with an active site binding preference for molecules in which a more coplanar relationship exists between the aromatic ring and the amine nitrogen. From the findings of this study, it appears that norepinephrine has a different active site binding orientation than most known substrates and competitive inhibitors of PNMT.

AbstractDie Grundkörper (Va) und (Xa) bzw. die stereoisomeren Trifluormethyl‐benzobicycloheptene (Ia) bis (IVa) bzw. (VIa)‐(lXa) werden mit Phthalimid in Gegenwart von Triphenylphos‐ phin und Azodicarbonsäureester zu den Phthalimiden (Ib)‐(Xb) umgesetzt, wobei allerdings nur teilweise eine stereospezifische Umsetzung erfolgt.

Abstract13C nuclear magnetic resonance spectra were collected for a series of 5‐ and 6‐monoaromatic ring‐substituted benzonorbornadienes and 5‐, 6‐, 7‐, and 8‐monosubstituted benzonorbornen‐2‐ones. 13C chemical shifts values were found to be useful in the differentiation of the four monosubstituted aromatic ring isomers of benzonorbornen‐2‐one (1). We found that the 13C NMR spectrum of a substituted benzonorbornen‐2‐one (A) could be predicted with good accuracy (R2 for each aromatic carbon ≥ 0.925) from a knowledge of the 13C NMR spectrum of 1 and the appropriately substituted benzene. The substituents studied were NO2, NH2, I, CF3, CN, OCH3, and H. Correlation analysis showed that the carbonyl in A was effectively insulated from the ring π‐system.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTPronounced pharmacological differences arising from minor structural changes in conformationally defined amphetamine analogs. Comparative evaluation of endo- and exo-2-amino- and endo- and exo-2-(methylamino)benzobicyclo[2.2.1]heptene and -benzobicyclo[2.2.2]octene analogs. Conformationally defined adrenergic agents. 4Gary L. Grunewald, Thomas J. Reitz, Augusta Hallett, Charles O. Rutledge, Sheila Vollmer, James M. Archuleta III, and James A. RuthCite this: J. Med. Chem. 1980, 23, 6, 614–620Publication Date (Print):June 1, 1980Publication History Published online1 May 2002Published inissue 1 June 1980https://pubs.acs.org/doi/10.1021/jm00180a006https://doi.org/10.1021/jm00180a006research-articleACS PublicationsRequest reuse permissionsArticle Views115Altmetric-Citations15LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts

AbstractAus dem Benzonorbornadien (I) erhält man über das Azid (II) das exo‐Aminoderivat (III).

In order to assess the importance of the aromatic rings in inhibition of neuronal amine uptake produced by tricyclic antidepressant drugs, derivatives of imipramine (IMI) and dcsipramine (DMI) were prepared in which either one (IMIH, DMIH) or both (IMIH2, DMIH2) of the aromatic rings were fully reduced to cyclohexane rings. The relative abilities of these compounds to inhibit the uptake of l-[3H]-norepinephrine (NE), [3H]-dopamine (DA) and [3H]-5-hydroxytryptamine (5-HT) into chopped tissue of rat cerebral cortex were determined. Reduction of one or both aromatic rings did not alter significantly the inhibition of uptake of [3H]-DA or [3H]5-HT produced by either IMI or DMI (IC50 values 25–80 μM). However, saturation of one or both rings abolished the selectivitv of DMI for inhibition of NE uptake (IC50 0.12 μM). decreasing potency 150-fold (IC50 18.3 μM) and 250-fold (IC50 29.4 μM) respectively. The effect of aromatic ring reduction on the IMI-induced inhibition of NE uptake was much less pronounced. The results suggest that hydrophobic rather than π-electron attractive forces are involved in the interaction of DMI or IMI with DA or 5-HT uptake sites. However, the loss in selectivity for inhibition of NE uptake upon reduction of DMI may reflect loss of π-electron interactions in the binding of DMI to the NE uptake site, or may reflect increased sensitivity to spatial disposition of the hydrophobic binding areas of the drug relative to that found at the DA or 5-HT amine uptake sites.