Effect of N-alkylation on the affinities of analogues of spiperone for dopamine D2 and serotonin 5-HT2 receptors.
Two series of N-substituted spiperone analogues were prepared and evaluated in vitro to measure their affinities for dopamine D2 and serotonin 5-HT2 receptors. Substitution of the amide nitrogen with an alkyl group of five carbon units or less resulted in analogues displaying a low selectivity for D2 compared to 5-HT2 receptors. However, a moderate improvement in selectivity for D2 receptors was observed with N-benzylspiperone. Substitution at either the ortho or para position of the benzyl group resulted in a further reduction in affinity for 5-HT2 receptors and improvement in the selectivity ratio. Examination of N-substituted analogues of spiperone may provide insights into the topography of the antagonist binding region of the 5-HT2 receptor. The results also suggest that an 18F-labeled analogue of N-(4-nitrobenzyl)spiperone (4p) may be a suitable tracer for studying D2 receptors with positron emission tomography since this compound displays a high selectivity for D2 receptors relative to that of spiperone and N-methylspiperone.
Mach
R H
RH
Cerebrovascular Research Center, University of Pennsylvania, Philadelphia 19104-6063.
Jackson
J R
JR
Luedtke
R R
RR
Ivins
K J
KJ
Molinoff
P B
PB
Ehrenkaufer
R L
RL
D000478:Alkylation; D011954:Receptors, Dopamine / Q000378:metabolism*; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin / Q000378:metabolism*; D013134:Spiperone / Q000031:analogs & derivatives* / Q000378:metabolism; D013329:Structure-Activity Relationship
D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D013134:Spiperone