TY - JOUR
T1 - Conformationally-flexible benzamide analogues as dopamine D3 and σ2 receptor ligands
AU - Mach, Robert H.
AU - Huang, Yunsheng
AU - Freeman, Rebekah A.
AU - Wu, Li
AU - Vangveravong, Suwanna
AU - Luedtke, Robert R.
N1 - Funding Information:
This research was funded by grants DA 12647 awarded by the National Institute on Drug Abuse and DAMD17-01-1-0446 awarded by the Department of Defense Breast Cancer Research Program of the US Army Medical Research and Materiel Command Office.
PY - 2004/1/5
Y1 - 2004/1/5
N2 - A series of conformationally-flexible analogues was prepared and their affinities for D2-like dopamine (D2, D3 and D 4) were determined using in vitro radioligand binding assays. The results of this structure-activity relationship study identified one compound, 15, that bound with high affinity (Ki value=2 nM) and moderate selectivity (30-fold) for D3 compared to D2 receptors. In addition, this series of compounds were also tested for affinity at σ 1 and σ2 receptors. We evaluated the affinity of these dopaminergic compounds at sigma receptors because (a) several antipsychotic drugs, which are high affinity antagonists at dopamine D 2-like receptors, also bind to sigma receptors and (b) sigma receptors are expressed ubiquitously and at high levels (picomoles per mg proteins). It was observed that a number of analogues displayed high affinity and excellent selectivity for σ2 versus σ1 receptors. Consequently, these novel compounds may be useful for characterizing the functional role of σ2 receptors and for imaging the σ2 receptor status of tumors in vivo with PET.
AB - A series of conformationally-flexible analogues was prepared and their affinities for D2-like dopamine (D2, D3 and D 4) were determined using in vitro radioligand binding assays. The results of this structure-activity relationship study identified one compound, 15, that bound with high affinity (Ki value=2 nM) and moderate selectivity (30-fold) for D3 compared to D2 receptors. In addition, this series of compounds were also tested for affinity at σ 1 and σ2 receptors. We evaluated the affinity of these dopaminergic compounds at sigma receptors because (a) several antipsychotic drugs, which are high affinity antagonists at dopamine D 2-like receptors, also bind to sigma receptors and (b) sigma receptors are expressed ubiquitously and at high levels (picomoles per mg proteins). It was observed that a number of analogues displayed high affinity and excellent selectivity for σ2 versus σ1 receptors. Consequently, these novel compounds may be useful for characterizing the functional role of σ2 receptors and for imaging the σ2 receptor status of tumors in vivo with PET.
KW - Atypical antipsychotics
KW - Dopamine D receptors
KW - σ receptors
UR - http://www.scopus.com/inward/record.url?scp=0348147638&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2003.09.083
DO - 10.1016/j.bmcl.2003.09.083
M3 - Article
C2 - 14684327
AN - SCOPUS:0348147638
SN - 0960-894X
VL - 14
SP - 195
EP - 202
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 1
ER -