TY - JOUR
T1 - Evaluation of N-phenyl homopiperazine analogs as potential dopamine D 3 receptor selective ligands
AU - Li, Aixiao
AU - Mishra, Yogesh
AU - Malik, Maninder
AU - Wang, Qi
AU - Li, Shihong
AU - Taylor, Michelle
AU - Reichert, David E.
AU - Luedtke, Robert R.
AU - MacH, Robert H.
N1 - Funding Information:
This research was funded by DA023957, MH081281 and DA29840 awarded by the National Institutes of Health .
PY - 2013/6/1
Y1 - 2013/6/1
N2 - A series of N-(2-methoxyphenyl)homopiperazine analogs was prepared and their affinities for dopamine D2, D3, and D4 receptors were measured using competitive radioligand binding assays. Several ligands exhibited high binding affinity and selectivity for the D3 dopamine receptor compared to the D2 receptor subtype. Compounds 11a, 11b, 11c, 11f, 11j and 11k had Ki values ranging from 0.7 to 3.9 nM for the D3 receptor with 30- to 170-fold selectivity for the D 3 versus D2 receptor. Calculated log P values (log P = 2.6-3.6) are within the desired range for passive transport across the blood-brain barrier. When the binding and the intrinsic efficacy of these phenylhomopiperazines was compared to those of previously published phenylpiperazine analogues, it was found that (a) affinity at D2 and D3 dopamine receptors generally decreased, (b) the D3 receptor binding selectivity (D2:D3 Ki value ratio) decreased and, (c) the intrinsic efficacy, measured using a forskolin-dependent adenylyl cyclase inhibition assay, generally increased.
AB - A series of N-(2-methoxyphenyl)homopiperazine analogs was prepared and their affinities for dopamine D2, D3, and D4 receptors were measured using competitive radioligand binding assays. Several ligands exhibited high binding affinity and selectivity for the D3 dopamine receptor compared to the D2 receptor subtype. Compounds 11a, 11b, 11c, 11f, 11j and 11k had Ki values ranging from 0.7 to 3.9 nM for the D3 receptor with 30- to 170-fold selectivity for the D 3 versus D2 receptor. Calculated log P values (log P = 2.6-3.6) are within the desired range for passive transport across the blood-brain barrier. When the binding and the intrinsic efficacy of these phenylhomopiperazines was compared to those of previously published phenylpiperazine analogues, it was found that (a) affinity at D2 and D3 dopamine receptors generally decreased, (b) the D3 receptor binding selectivity (D2:D3 Ki value ratio) decreased and, (c) the intrinsic efficacy, measured using a forskolin-dependent adenylyl cyclase inhibition assay, generally increased.
KW - D dopamine receptors
KW - D-like receptors
KW - Dopamine
KW - Homopiperazine analogs
KW - Receptor subtype selective ligands
UR - http://www.scopus.com/inward/record.url?scp=84877820423&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2013.03.074
DO - 10.1016/j.bmc.2013.03.074
M3 - Article
C2 - 23618707
AN - SCOPUS:84877820423
SN - 0968-0896
VL - 21
SP - 2988
EP - 2998
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 11
ER -