(-CIS-N-(PARA, META, AND ORTHO SUBSTITUTED BENZYL)-N-NORMETAZOCINES SYNTHESIS AND BINDING-AFFINITY AT THE [H-3] (+)-PENTAZOCINE-LABELED (SIGMA-1)-SITE AND QUANTITATIVE STRUCTURE-AFFINITY RELATIONSHIP STUDIES())

sigma l receptor ligands have potential pharmacological significance a s antipsychotic drugs, as tools in the study of drug-induced motor fun ction disorders, and as radiopharmaceutical imaging agents for the non invasive imaging of malignant tumors in human subjects. A series of su bstituted N-benzyl-N-normetazocines were synthesized and their binding affinity at the sigma l receptor evaluated in order to examine the de tails of the structure-affinity relationships (SAR) of a previously de termined high-affinity lead compound, (+)-cis-N-benzyl-N-normetazocine (K-i = 0.67 nM). Variation in the benzyl substituents of these compou nds produced a 1590-fold range in affinity at the sigma l receptor fro m the unsubstituted benzyl analog to the lowest affinity p-tert-butylb enzyl analog (K-i - 1066 nM). The nanomolar binding affinity for the s igma l receptor of (+)-cis-N-(4-fluorobenzyl)-N-normetzocine suggests that this analog may be a useful PET imaging agent.