Synthesis and quantitative structure-activity relationships of N-(1-benzylpiperidin-4-yl)phenylacetamides and related analogues as potent and selective sigma1 receptor ligands.
A series of N-(1-benzylpiperidin-4-yl)phenylacetamide derivatives was synthesized and evaluated for affinity at sigma1 and sigma2 receptors. Most of these compounds showed a high affinity for sigma1 receptors and a low to moderate affinity for sigma2 receptors. The unsubstituted compound N-(1-benzylpiperidin-4-yl)phenylacetamide, 1, displayed a high affinity and selectivity for sigma1 receptors (Ki values of 3.90 nM for sigma1 receptors and 240 nM for sigma2 receptors). The influence of substitutions on the phenylacetamide aromatic ring on binding at both the sigma1 and sigma2 receptor has been examined through Hansch-type quantitative structure-activity relationship (QSAR) studies. In general, all 3-substituted compounds, except for the OH group, had a higher affinity for both sigma1 and sigma2 receptors when compared with the corresponding 2- and 4-substituted analogues. The selectivity for sigma1 receptors displayed a trend of 3 > 2 approximately 4 for Cl, Br, F, NO2, and OMe substituted analogues. Halogen substitution on the aromatic ring generally increased the affinity for sigma2 receptors while maintaining a similar affinity for sigma1 receptors. Substitution with electron-donating groups, such as OH, OMe, or NH2, resulted in weak or negligible affinity for sigma2 receptors and a moderate affinity for sigma1 receptors. The 2-fluoro-substituted analogue, 11, exhibited the highest selectivity for sigma1 receptors among all compounds tested, with a Ki value of 3.56 nM for sigma1 receptors and 667 nM for sigma2 receptors. Compounds 1, 5, 9, 11, and 20 had no affinity for dopamine D2 (IC50 > 10 000 nM) and D3 (IC50 > 10 000 nM) receptors. The nanomolar binding affinity and high selectivity for sigma1 receptors suggest that these compounds may be developed as potential radiotracers for positron emission tomography or single photon emission computerized tomography imaging studies.
Huang
Y
Y
Department of Radiology-PET Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
Hammond
P S
PS
Whirrett
B R
BR
Kuhner
R J
RJ
Wu
L
L
Childers
S R
SR
Mach
R H
RH
D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D000083:Acetanilides; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D006168:Guinea Pigs; D008024:Ligands; D008099:Liver / Q000378:metabolism; D008297:Male; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000081:Acetamides; D000083:Acetanilides; D001549:Benzamides; D008024:Ligands; C112868:N-(1-benzylpiperidin-4-yl)phenylacetamide; D010880:Piperidines; D017448:Receptors, Dopamine D2; D017480:Receptors, sigma; C088152:N-(N-benzylpiperidin-4-yl)-4-iodobenzamide