Zhang Shijun, Zhen Juan, Reith Maarten E A, Dutta Aloke K
Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI 48202, USA.
Bioorg Med Chem. 2004 Dec 1;12(23):6301-15. doi: 10.1016/j.bmc.2004.07.069.
In our effort to delineate novel pharmacophoric configuration of bioisosteric pyran versions of cis-(6-benzhydryl-piperidin-3-yl)-benzylamine derivatives in interacting with the monoamine transporter, further structure-activity relationship study was carried out. Both cis and trans 2,4- and 3,6-disubstituted derivatives were synthesized to determine the positional importance of N-substitution on affinity for monoamine transporters, that is the dopamine transporter (DAT), the serotonin transporter (SERT), and the norepinephrine transporter (NET) in rat brain. For that purpose, the potency of compounds was determined in competing for the binding of [(3)H]WIN 35,428, [(3)H]citalopram, and [(3)H]nisoxetine, respectively. Selected compounds were also evaluated for their activity in inhibiting the uptake of [(3)H]DA by DAT. Our binding results demonstrated potency in 3,6-disubstituted derivatives while 2,4-disubstituted derivatives failed to exhibit any appreciable binding affinity. Further structural exploration of the exocyclic N-atom in 3,6-disubstituted derivatives produced compounds potent at both DAT and NET. Compounds 16h and 16o with hydroxyl and amino groups in the phenyl moiety of the benzyl group produced the highest activity for the NET. In this regard, compound 16e with a methoxy substituent produced weak affinity at NET, which upon conversion into a hydroxyl functionality as in 16h produced potent affinity for the NET. Various indole derivatives displayed different interactions; the 5-substituted indole derivative 16n exerted potent affinity for NET, confirming the bioisosteric equivalence between this indole moiety and the phenyl-4-hydroxy group in 16h.
为了描绘顺式-(6-二苯甲基哌啶-3-基)-苄胺衍生物的生物电子等排体吡喃变体与单胺转运体相互作用时的新型药效团构型，我们进一步开展了构效关系研究。合成了顺式和反式2,4-以及3,6-二取代衍生物，以确定N-取代基位置对大鼠脑中多巴胺转运体（DAT）、5-羟色胺转运体（SERT）和去甲肾上腺素转运体（NET）等单胺转运体亲和力的重要性。为此，分别测定了化合物与[(3)H]WIN 35,428、[(3)H]西酞普兰和[(3)H]尼索西汀结合的竞争能力。还评估了所选化合物抑制DAT摄取[(3)H]DA的活性。我们的结合结果表明3,6-二取代衍生物具有活性，而2,4-二取代衍生物未表现出任何明显的结合亲和力。对3,6-二取代衍生物中环外N原子的进一步结构探索产生了对DAT和NET均有效的化合物。苄基苯基部分带有羟基和氨基的化合物16h和16o对NET表现出最高活性。在这方面，带有甲氧基取代基的化合物16e对NET亲和力较弱，将其转化为如16h中的羟基官能团后，对NET产生了强效亲和力。各种吲哚衍生物表现出不同的相互作用；5-取代吲哚衍生物16n对NET具有强效亲和力，证实了该吲哚部分与16h中苯基-4-羟基之间的生物电子等排等效性。
