Biaryl analogues of conformationally constrained tricyclic tropanes as potent and selective norepinephrine reuptake inhibitors: synthesis and evaluation of their uptake inhibition at monoamine transporter sites.
Biaryl analogues of conformationally constrained tricyclic tropanes as potent and selective norepinephrine reuptake inhibitors: synthesis and evaluation of their uptake inhibition at monoamine transporter sites.
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构象受限的三环托烷的联芳基类似物作为有效的选择性去甲肾上腺素再摄取抑制剂：合成和评估其在单胺转运蛋白位点的摄取抑制。
DOI：
10.1021/jm020596w
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发表时间：
2003
期刊：
影响因子：
--
通讯作者：
Kozikowski,AlanP
中科院分区：
文献类型：
--
作者：
Zhou,Jia;Zhang,Ao;Klass,Thomas;Johnson,KennethM;Wang,ChengZ;Ye,YanPing;Kozikowski,AlanP
A series of novel conformationally constrained tricyclic tropane derivatives containing a biaryl moiety, (Z)-9-(biarylylmethylene)-7-azatricyclo[4.3.1.03,7]decanes, were synthesized and evaluated for their ability to inhibit reuptake of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) by the DA, 5-HT, and NE transporters. Most of the compounds containing a methoxycarbonyl substituent at C-10 exhibit moderate to high inhibitory activity at the NET but lower activity at the DAT and SERT. Among these new compounds, some potent, NET-selective ligands were identified. Thep-methoxy derivative11ahas aKivalue of 39 nM for uptake inhibition at the NET and moderate to high selectivity over the SERT (100-fold) and the DAT (20-fold). Compound11fexhibits a remarkable potency (Ki= 9.7 nM) at the NET and a 25-fold selectivity over both the SERT and the DAT. Analogue23containing a thiophene ring as a bioisosteric replacement of the phenyl ring Ar displays a high activity (Ki= 10.3 nM) for the NET and similar selectivity over the SERT (50-fold) and the DAT (37-fold). The selectivity profile of biaryl analogues differs from that of the monoaryl series, as most members of that series display excellent potency at and selectivity for the SERT (J. Med. Chem.2002,45, 1930). This finding suggests that the different shape and size of the lipophilic recognition pocket that encompasses the aryl ring(s) of these tropanes are major determinants of a ligand's transporter activity at either the NET or the SERT. Some of the compounds in this series may also be valuable in sorting out the contribution of the individual transporters to cocaine's reinforcing properties.
