Grunewald G L, Caldwell T M, Li Q, Criscione K R
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045, USA.
J Med Chem. 1999 Aug 26;42(17):3315-23. doi: 10.1021/jm980734a.
A series of 3-trifluoromethyl-1,2,3,4-tetrahydroisoquinolines was synthesized and evaluated as inhibitors of phenylethanolamine N-methyltransferase (PNMT) and as inhibitors of the binding of clonidine at the alpha(2)-adrenoceptor. These compounds were found to be selective inhibitors of PNMT due to their decreased affinity for the alpha(2)-adrenoceptor, which was attributed to steric bulk intolerance around the 3-position of 1,2,3,4-tetrahydroisoquinoline (THIQ) at the alpha(2)-adrenoceptor and to the decreased pK(a) of the THIQ amine due to the 3-trifluoromethyl moiety. Overall, these compounds displayed less affinity for PNMT compared to previously studied THIQ-type inhibitors, except for 16 which was found to have good affinity for PNMT (PNMT K(i) = 0.52 microM). Compounds 14 and 16 proved to be the most selective inhibitors in this small series of compounds and are some of the most selective inhibitors of PNMT known (14, selectivity alpha(2) K(i)/PNMT K(i) = 700; 16, selectivity alpha(2) K(i)/PNMT K(i) > 1900). Compounds 14 and 16 are also quite lipophilic due to the 3-trifluoromethyl moiety and represent promising new leads for the development of new highly selective inhibitors of PNMT, which should be sufficiently lipophilic to penetrate the blood-brain barrier.
合成了一系列3 - 三氟甲基 - 1,2,3,4 - 四氢异喹啉，并对其作为苯乙醇胺N - 甲基转移酶（PNMT）抑制剂以及可乐定与α(2) - 肾上腺素能受体结合的抑制剂进行了评估。由于这些化合物对α(2) - 肾上腺素能受体的亲和力降低，被发现是PNMT的选择性抑制剂，这归因于α(2) - 肾上腺素能受体处1,2,3,4 - 四氢异喹啉（THIQ）3位周围的空间位阻不耐受以及由于3 - 三氟甲基部分导致THIQ胺的pK(a)降低。总体而言，与先前研究的THIQ型抑制剂相比，这些化合物对PNMT的亲和力较低，除了16被发现对PNMT具有良好的亲和力（PNMT K(i) = 0.52 microM）。在这一小系列化合物中，化合物14和16被证明是最具选择性的抑制剂，并且是已知的一些最具选择性的PNMT抑制剂（14，选择性α(2) K(i)/PNMT K(i) = 700；16，选择性α(2) K(i)/PNMT K(i) > 1900）。由于3 - 三氟甲基部分，化合物14和16也相当亲脂，代表了开发新型高选择性PNMT抑制剂的有前景的新先导物，这些抑制剂应具有足够的亲脂性以穿透血脑屏障。
