(+)-cis-N-(para-, meta-, and ortho-substituted benzyl)-N-normetazocines: synthesis and binding affinity at the [3H]-(+)-pentazocine-labeled (sigma 1) site and quantitative structure-affinity relationship studies.
sigma 1 receptor ligands have potential pharmacological significance as antipsychotic drugs, as tools in the study of drug-induced motor function disorders, and as radiopharmaceutical imaging agents for the noninvasive imaging of malignant tumors in human subjects. A series of substituted N-benzyl-N-normetazocines were synthesized and their binding affinity at the sigma 1 receptor evaluated in order to examine the details of the structure--affinity relationships (SAR) of a previously determined high-affinity lead compound, (+)-cis-N-benzyl-N-normetazocine (Ki = 0.67 nM). Variation in the benzyl substituents of these compounds produced a 1590-fold range in affinity at the sigma 1 receptor from the unsubstituted benzyl analog to the lowest affinity p-tert-butylbenzyl analog (Ki = 1066 nM). The nanomolar binding affinity for the sigma 1 receptor of (+)-cis-N-(4-fluorobenzyl)-N-normetzocine suggests that this analog may be a useful PET imaging agent.
Chemistry and Life Sciences, Research Triangle Institute, North Carolina 27709.
S W
SW
Mascarella
X
X
Bai
W
W
Williams
B
B
Sine
W D
WD
Bowen
F I
FI
Carroll
D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D003496:Cyclazocine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D009294:Narcotics / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010423:Pentazocine / Q000737:chemistry* / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014316:Tritium
D009294:Narcotics; D017480:Receptors, sigma; D014316:Tritium; C014716:normetazocine; D003496:Cyclazocine; D010423:Pentazocine