Importance of the aromatic ring in adrenergic amines. 6. Nonaromatic analogs of phenylethanolamine as inhibitors of phenylethanolamine N-methyltransferase: role of .pi.-electronic and steric interactions

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Abstract
To probe the importance of .pi.-electronic and steric interactions of nonaromatic analogs of phenylethanolamine as inhibitors of phenylethanolamine N-methyltransferase (PNMT), a series of norbornane and norbornene ethanolamines was prepared and evaluated as inhibitors of PNMT (liquid chromatographic-electrochemical detector assay). A major importance of hydrophobic interaction of the ring moiety attached to the ethanolamine side chain was indicated previously, but a possible importance of .pi.-complex formation could have been obscured by conformational differences among the analogs. Norbornane and norbornene substituted with an ethanolamine side chain at positions 1,2-exo and 2-endo were prepared from the corresponding aldehydes by addition of trimethylsilyl cyanide (Me3SiCN) and lithium aluminum hydride reduction. The saturated (norbornane) analogs were 2 times more potent as inhibitors of the enzyme than were the norbornene analogs, thus suggesting that .pi.-complex formation is not an important contribution to binding and, as previously proposed, a hydrophobic interaction is the significant binding interaction of the ring moiety. The hydrophobic binding area has a critical size that requires the hydrophobic moiety to be of sufficient length; the bridgehead-substituted norbornane and norbornene ethanolamines was too short for optimal binding. The 2-exo orientation of the ethanolamine side chain was preferred to the 2-endo orientation, supporting the hypothesis that the ring moiety prefers to be oriented away from the side chain. [PNMT is involved in epinephrine synthesis.].
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