A series of lobelane and GZ-793A analogues that incorporate aromatic 4-hydroxy and 4-(2-fluoroethoxy) substituents were synthesized and evaluated for inhibition of [3H]dopamine (DA) uptake at the vesicular monoamine transporter-2 (VMAT2) and the dopamine transporter (DAT), and [3H]serotonin uptake at the serotonin transporter (SERT). Most of these compounds exhibited potent inhibition of DA uptake at VMAT2 in the nanomolar range (Ki = 30-70 nM). The two most potent analogues, 7 and 14, both exhibited a Ki value of 31 nM for inhibition of VMAT2. The lobelane analogue 14, incorporating 4-(2-fluoroethoxy) and 4-hydroxy aromatic substituents, exhibited 96- and 335-fold greater selectivity for VMAT2 versus DAT and SERT, respectively, in comparison to lobelane. Thus, lobelane analogues bearing hydroxyl and fluoroethoxy moieties retain the high affinity for VMAT2 of the parent compound, while enhancing selectivity for VMAT2 versus the plasmalemma transporters.
|Number of pages||6|
|Journal||Bioorganic and Medicinal Chemistry Letters|
|State||Published - May 1 2016|
Bibliographical noteFunding Information:
This research was supported by NIH U01 DA13519 , 5T32 DA022981 , TR000117 and NIH/COBRA P20 GM109005 grants, and an Arkansas Research Alliance (ARA) Scholar award.
© 2016 Elsevier B.V. All rights reserved.
- 4-Hydroxyphenyl lobelane analogues
- Dopamine and serotonin transporter
- Dopamine uptake
- Fluorinated lobelane analogues
- Vesicular monoamine transporter-2
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry