Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase:  Balancing pK a and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-Fluorination

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 pK a of the THIQ amine from 9.53 (CH3) to 7.88 (CH2F), 6.42 (CHF2), and 4.88 (CF3). This decrease in pK a results in a reduction in affinity for the α2-adrenoceptor. However, increased fluorination also results in a reduction in PNMT inhibitory potency, apparently due to steric and electrostatic factors. Biochemical evaluation of a series of 3-fluoromethyl-THIQs and 3-trifluoromethyl-THIQs showed that the former were highly potent inhibitors of PNMT, but were often nonselective due to significant affinity for the α2-adrenoceptor, while the latter were devoid of α2-adrenoceptor affinity, but also lost potency at PNMT. 3-Difluoromethyl-7-substituted-THIQs have the proper balance of both steric and pK a properties and thus have enhanced selectivity versus the corresponding 3-fluoromethyl-7-substituted-THIQs and enhanced PNMT inhibitory potency versus the corresponding 3-trifluoromethyl-7-substituted-THIQs. Using the “Goldilocks Effect” analogy, the 3-fluoromethyl-THIQs are too potent (too hot) at the α2-adrenoceptor and the 3-trifluoromethyl-THIQs are not potent enough (too cold) at PNMT, but the 3-difluoromethyl-THIQs are just right. They are both potent inhibitors of PNMT and highly selective due to low affinity for the α2-adrenoceptor. This seems to be the first successful use of the β-fluorination of aliphatic amines to impart selectivity to a pharmacological agent while maintaining potency at the site of interest.