Grunewald Gary L, Seim Mitchell R, Lu Jian, Makboul Mariam, Criscione Kevin R
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045, USA.
J Med Chem. 2006 May 18;49(10):2939-52. doi: 10.1021/jm051262k.
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 alpha(2)-adrenoceptor. Fluorination of the methyl group lowers the pK(a) of the THIQ amine from 9.53 (CH(3)) to 7.88 (CH(2)F), 6.42 (CHF(2)), and 4.88 (CF(3)). This decrease in pK(a) results in a reduction in affinity for the alpha(2)-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 alpha(2)-adrenoceptor, while the latter were devoid of alpha(2)-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 alpha(2)-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 alpha(2)-adrenoceptor. This seems to be the first successful use of the beta-fluorination of aliphatic amines to impart selectivity to a pharmacological agent while maintaining potency at the site of interest.
3-甲基-1,2,3,4-四氢异喹啉（3-甲基-THIQs）是苯乙醇胺N-甲基转移酶（PNMT）的强效抑制剂，但由于对α₂-肾上腺素能受体具有显著亲和力而缺乏选择性。甲基的氟化作用使THIQ胺的pKa值从9.53（CH₃）降至7.88（CH₂F）、6.42（CHF₂）和4.88（CF₃）。pKa值的这种降低导致对α₂-肾上腺素能受体的亲和力下降。然而，氟化程度的增加也导致PNMT抑制效力降低，这显然是由于空间位阻和静电因素所致。对一系列3-氟甲基-THIQs和3-三氟甲基-THIQs的生化评估表明，前者是PNMT的高效抑制剂，但由于对α₂-肾上腺素能受体具有显著亲和力而常常缺乏选择性，而后者则缺乏对α₂-肾上腺素能受体的亲和力，但对PNMT也失去了效力。3-二氟甲基-7-取代-THIQs在空间位阻和pKa性质方面具有恰当的平衡，因此与相应的3-氟甲基-7-取代-THIQs相比具有更高的选择性，与相应的3-三氟甲基-7-取代-THIQs相比具有更高的PNMT抑制效力。用“金发姑娘效应”来类比，3-氟甲基-THIQs对α₂-肾上腺素能受体的作用太强（太热），而3-三氟甲基-THIQs对PNMT的作用则不够强（太冷），但3-二氟甲基-THIQs则恰到好处。它们既是PNMT的强效抑制剂，又由于对α₂-肾上腺素能受体的亲和力低而具有高度选择性。这似乎是首次成功利用脂肪胺的β-氟化作用赋予药物选择性，同时保持在目标位点的效力。
