Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing p K a and Steric Effects in …

GL Grunewald, MR Seim, J Lu, M Makboul…

Index: Grunewald, Gary L.; Seim, Mitchell R.; Lu, Jian; Makboul, Mariam; Criscione, Kevin R. Journal of Medicinal Chemistry, 2006 , vol. 49, # 10 p. 2939 - 2952

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Citation Number: 22

Abstract

3-Methyl-1, 2, 3, 4-tetrahydroisoquinolines (3-methyl-THIQs) are potent inhibitors of phenylethanolamine N-methyltransferase (PNMT), but are not selective due to significant affinity for the α2-adrenoceptor. Fluorination of the methyl group lowers the p K a of the THIQ amine from 9.53 (CH3) to 7.88 (CH2F), 6.42 (CHF2), and 4.88 (CF3). This decrease in p K a results in a reduction in affinity for the α2-adrenoceptor. However, increased fluorination ...